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Context: Neural mobilization is commonly used in sports, and previous studies have suggested that it has a positive impact on lower-limb flexibility and performance. However, studies exploring the effect of neural mobilization dosage are almost nonexistent. Objectives: This study aimed to assess whether 2 distinct dosages of neural gliding mobilization (4 and 8 sets of 10 repetitions) impact the flexibility and performance of both the mobilized and nonmobilized lower limb in basketball athletes differently. Design: Randomized, parallel, and single-blinded study. Setting: Amateur and professional basketball clubs. Participants: Fifty-two basketball athletes (40 men and 12 women), who were distributed into 2 groups; one received 40 (n = 28) and the other 80 repetitions (n = 24) of neural gliding mobilization. Intervention: Neural gliding mobilization applied to a single limb (the dominant limb). Main Outcome Measures: Knee extension angle for hamstring flexibility; hop tests and single-leg vertical jump for performance. Results: There was a significant main effect of time (P <.001), a significant interaction between time and limb for flexibility (P =.003), and a significant interaction between time and limb for the single-leg hop test (P =.032). No other significant main effect for any of the remaining variables was found (P >.05). Conclusions: The application of both 40 repetitions and 80 of neural gliding significantly improved lower-limb flexibility, and one was not superior to the other. Neither one dosage nor the other positively or negatively impacted the lower-limb performance of basketball athletes. [ABSTRACT FROM AUTHOR]

Work on collective action focuses mainly on the perspective of disadvantaged groups. However, the dynamics of social change cannot be fully understood without taking into account the reactions of the members of advantaged groups to collective action by low-status groups. In 10 experiments conducted in 4 different intergroup contexts (N = 1349), we examine advantaged groups support for normative versus non-normative collective action by disadvantaged groups. Experiments 1a to 1e show that normative collective action is perceived as more likely to improve the disadvantaged group's position and that non-normative collective action is perceived as more damaging to the advantaged group's social image. Also, these differences are due to differences in perceptions of actions violating norms of protest and perceptions of protesters as blaming the advantaged group for the inequality. Experiments 2a to 3 show that high compared with low identified members of advantaged groups distinguish more between types of collective action, showing a greater preference for the normative type. Both a mediational design and an experimental-causal-chain design (Experiments 3 and 4) show that support among high identifiers depends more on whether collective action damages the high-status group's social image than on whether it actually reduces inequality. Findings suggest that high-status groups' support for collective action is not only shaped by the perceived likelihood of change but also by its potential damage to the image of the high-status ingroup. [ABSTRACT FROM AUTHOR]

The 21st century has seen unprecedented levels of mass protest all over the world. Protest is a dynamic interplay of actions over time, across levels of society (e.g., individual, interpersonal, group, intergroup), and across domains (e.g., social, cultural, political, economic). To illustrate this systems view, we first describe the local and global ecology of protest as it operates in the world now. We rely mainly on macro-level social science research to describe the scale and scope of specific movements (e.g., Black Lives Matter) as well as temporal trends in protest across the world. Second, we offer an expansive conceptualization of the types of protest, and the consequences of protest, based on an integrative review of micro- and meso-level research in psychology, and macro-level research in social science. Third, we present a temporal social network analysis of the emergence of the Black Lives Matter movement as an empirical example of a systems approach. [ABSTRACT FROM AUTHOR]

As the incidence of diabetes continues to increase in the western world, the prevalence of chronic wounds related to this condition continues to be a major focus of wound care research. Additionally, over 50% of chronic wounds exhibit signs and symptoms that are consistent with localized bacterial biofilms underlying severe infections that contribute to tissue destruction, delayed wound-healing and other serious complications. Most current biomedical approaches for advanced wound care aim at providing antimicrobial protection to the open wound together with a matrix scaffold (often collagen-based) to boost reestablishment of the skin tissue. Therefore, the present review is focused on the efforts that have been made over the past years to find peptides possessing wound-healing properties, towards the development of new and effective wound care treatments for diabetic foot ulcers and other skin and soft tissue infections. [ABSTRACT FROM AUTHOR]

Disadvantaged groups use different means to protest inequality. Normative protest is more likely when the societal context of inter-group inequality signals that there is opportunity for status improvement. Non-normative protest is more likely to occur in systems in which status improvement is unlikely. However, little is known about how advantaged groups react to (normative vs. non-normative) protest as a function of the likelihood for status improvement of the disadvantaged offered by the context (high vs. low). Four experiments (N = 1092) assessed endorsement of protest among advantaged group members using different operationalizations of likelihood for status improvement and type of protest in four different intergroup contexts. Advantaged group members scoring lower in self-investment in their group identity endorsed protest more when the form of protest matched likelihood for status improvement than when it did not. Specifically, less invested members most supported normative protest (i.e., marches, petitions) when likelihood for status improvement was high and non-normative protest (i.e., hacking, destruction of property) occurring in contexts in which status improvement was unlikely. Highly self-invested individuals tended to be unaffected by the form of protest or type of inequality. Mediated moderation analyses suggested that increased appraisals of illegitimacy of inequality explained why support (i.e. among the less invested) was higher when the form of protest fitted opportunity for societal improvement. Results suggest that those less committed to their advantaged position jointly consider type of protest and its context of occurrence when forming opinions on acceptability of disadvantaged protest. • Only less invested advantaged members are sensitive to the context of protest. • Normative protest is acceptable when status improvement is likely. • Non-Normative protest is acceptable when status improvement is unlikely. • Acceptability of protest is reflected on legitimacy and support. • The less invested see inequality as more illegitimate when protest and context fit. [ABSTRACT FROM AUTHOR]

HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules. [ABSTRACT FROM AUTHOR]

This study aimed to better understand couples’ satisfaction. We hypothesized that similar levels on the two dimensions of fear of intimacy (fear of losing the self [FLS] and fear of losing the other [FLO]) would buffer the negative association between fear of intimacy and relationship satisfaction. Findings revealed a positive influence in relationship satisfaction from partner similarity in FLS. No effects were found from partner similarity in FLO. Relationship satisfaction decreased when one partner’s higher fear of losing the self was combined with lower fear of losing the other from the other partner. Repercussions for couple therapy are discussed. [ABSTRACT FROM PUBLISHER]

Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system development, such sensitive periods shape the formation of neurocircuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint as well as the environmental context. While allowing for adaptation, such sensitive periods are also vulnerability windows during which external and internal factors can confer risk to disorders by derailing otherwise resilient developmental programs. Here we review developmental periods that are sensitive to monoamine signaling and impact adult behaviors of relevance to psychiatry. Specifically, we review (1) a serotonin-sensitive period that impacts sensory system development, (2) a serotonin-sensitive period that impacts cognition, anxiety- and depression-related behaviors, and (3) a dopamine- and serotonin-sensitive period affecting aggression, impulsivity and behavioral response to psychostimulants. We discuss preclinical data to provide mechanistic insight, as well as epidemiological and clinical data to point out translational relevance. The field of translational developmental neuroscience has progressed exponentially providing solid conceptual advances and unprecedented mechanistic insight. With such knowledge at hand and important methodological innovation ongoing, the field is poised for breakthroughs elucidating the developmental origins of neuropsychiatric disorders, and thus understanding pathophysiology. Such knowledge of sensitive periods that determine the developmental trajectory of complex behaviors is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

The article presents brief information on recycling of drugs for malaria. Topics discussed include chemical recycling of quinine, synthetic blood-stage antimalarial acridines named Quinacrine, and synopsis of clinically relevant antimalarial 4-aminoquinolines. Also talks about computational studies on antimalarial classics and their analogues, and rescuing and repurposing drugs used in malaria such as antitumorals and antiretrovirals.

In the 80s Guinea-Bissau had to be submitted to Structural Adjustment Programmes proposed by the World Bank and the IMF. It is known that the development requires order, democracy, state of law, features that are not present in Guinea-Bissau, where opposition to political power has been systematically carried out by military power through coups, assassinations and all kinds of violence. The censuses of 1950 and 1991, analyzed in the context of the Global Collaboratory on the History of Labour Relations (1500-200) and which constitute the essential sources to the development of this article, are revealing of the relations of production that have developed and still develop in the context of a late capitalism and fragile country [ABSTRACT FROM AUTHOR]

Highlights: [•] The binding mode of piperazine derivatives with HIV-1 gp120 was predicted. [•] Impact of their conformational flexibility in their anti-HIV activity was inquired. [•] Results suggested their flexibility is more important than it has been assumed. [Copyright &y& Elsevier]

Abstract: Novel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine. The compounds were not toxic to human hepatoma cells at concentrations up to 5μM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria. [Copyright &y& Elsevier]

In two experiments, we analyzed the use of intra-group differentiation between normative and deviant members as an identity mobilization strategy in intergroup negotiations. Because ingroup members sometimes try to obtain the support of outgroup audiences to attain their goals, we propose that in intergroup negotiations, people attempt to minimize the distinction between the parties involved by changing the appraisal of deviance and including deviant members in the ingroup's prototype. In line with this hypothesis, differences in the assessment of typicality between normative and deviant targets were reduced in instrumental intergroup negotiation contexts. Furthermore, we explored a boundary condition for this effect and found that such outgroup approach is disrupted when threats taint the intergroup negotiation context. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The control of malaria is challenged by drug resistance,and newantimalarial drugs are needed. New drug discovery efforts includeconsideration of hybrid compounds as potential multitarget antimalarials.Previous work from our group has demonstrated that hybrid structuresresulting from cinnamic acid conjugation with heterocyclic moietiesfrom well-known antimalarials present improved antimalarial activity.Now, we report the synthesis and SAR analysis of an expanded seriesof cinnamic acid derivatives displaying remarkably high activitiesagainst both blood- and liver-stage malaria parasites. Two compoundsjudged most promising, based on their in vitro activity and druglikenessaccording to the Lipinski rules and Veber filter, were active in vivoagainst blood-stage rodent malaria parasites. Therefore, the compoundsreported represent a new entry as promising dual-stage antimalarialleads. [ABSTRACT FROM AUTHOR]

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression. [ABSTRACT FROM AUTHOR]

In the adult hippocampal dentate gyrus, newborn granule cells grow dendrites into the molecular layer and send axons into the CA3 region. Several molecular markers have been used to analyze production of these new neurons; however, no good markers for new axons have been described. Here we demonstrate that tau protein isoform with three microtubule binding domains (3R-Tau) is a marker of those axons following an antigen retrieval protocol. By using retrovirus-mediated GFP transduction, GFP can be detected in a period of 7-14 days after viral infection. We also provide a 'proof of principle' demonstration of the power of that labeling showing modulation of 3R-Tau positive axons under physiological conditions (exercise and aging) as well as in a FTDP-17 neurodegenerative model and Alzheimer's disease models (mice overexpressing AβPPsw, ind or GSK3β). We conclude that 3R-Tau would be an efficient marker and a valuable tool to study new axons in adult neurogenesis as well as in neurodegenerative processes. [ABSTRACT FROM AUTHOR]

Abstract: A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain–inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites. [Copyright &y& Elsevier]

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult-generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult-generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult-generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus-dependent memory in intact mice. First, in the water maze task, rates of integration of adult-generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult-generated DGCs. Third, these findings generalized to another hippocampus-dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult-generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Despite the impact of schizophrenia and mood disorders, which in extreme cases can lead to death, recent decades have brought little progress in the development of new treatments. Recent studies have shown that Reelin, an extracellular protein that is critical for neuronal development, is reduced in schizophrenia and bipolar disorder patients. However, data on a causal or protective role of Reelin in psychiatric diseases is scarce. In order to study the direct influence of Reelin's levels on behavior, we subjected two mouse lines, in which Reelin levels are either reduced (Reelin heterozygous mice) or increased (Reelin overexpressing mice), to a battery of behavioral tests: open-field, black-white box, novelty-suppressed-feeding, forced-swim-test, chronic corticosterone treatment followed by forced-swim-test, cocaine sensitization and pre-pulse inhibition (PPI) deficits induced by N-methyl-D-aspartate (NMDA) antagonists. These tests were designed to model some aspects of psychiatric disorders such as schizophrenia, mood, and anxiety disorders. We found no differences between Reeler heterozygous mice and their wild-type littermates. However, Reelin overexpression in the mouse forebrain reduced the time spent floating in the forced-swim-test in mice subjected to chronic corticosterone treatment, reduced behavioral sensitization to cocaine, and reduced PPI deficits induced by a NMDA antagonist. In addition, we demonstrate that while stress increased NMDA NR2B-mediated synaptic transmission, known to be implicated in depression, Reelin overexpression significantly reduced it. Together, these results point to the Reelin signaling pathway as a relevant drug target for the treatment of a range of psychiatric disorders. [ABSTRACT FROM AUTHOR]

The article focuses on a study of the effect of deep brain stimulation (DBS) on increasing hippocampal neurogenesis. The study found that new granule cells, generated due to entorhinal cortex (EC) stimulation, grow normally and assume functional roles in hippocampal circuits supporting spatial memory. It also found that promotion of hippocampal neurogenesis induced by stimulation results in formation of spatial memory, suggesting pro-cognitive effects of DBS through enhanced neurogenesis.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model ( q = 0.696 and r = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields ( q = 0.711 and r = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials. [ABSTRACT FROM AUTHOR]

Abstract: The first anti-HIV drug, zidovudine (AZT), was approved by the FDA a quarter of a century ago, in 1985. Currently, anti-HIV drug-combination therapies only target HIV-1 protease and reverse transcriptase. Unfortunately, most of these molecules present numerous shortcomings such as viral resistances and adverse effects. In addition, these drugs are involved in later stages of infection. Thus, it is necessary to develop new drugs that are able to block the first steps of viral life cycle. Entry of HIV-1 is mediated by its two envelope glycoproteins: gp120 and gp41. Upon gp120 binding to cellular receptors, gp41 undergoes a series of conformational changes from a non-fusogenic to a fusogenic conformation. The fusogenic core of gp41 is a trimer-of-hairpins structure in which three C-terminal helices pack against a central trimeric-coiled coil formed by three N-terminal helices. The formation of this fusogenic structure brings the viral and cellular membranes close together, a necessary condition for membrane fusion to occur. As gp120 and gp41 are attractive targets, the development of entry inhibitors represents an important avenue of anti-HIV drug therapy. The present review will focus on some general considerations about HIV, the main characteristics of gp120, gp41 and their inhibitors, with special emphasis on the advances of computational approaches employed in the development of bioactive compounds against HIV-1 entry process. [Copyright &y& Elsevier]

Abstract: According to , instrumental goals refer to the maximization of profit whereas identity goals are associated with the attainment of a positive social identity. In two experiments, we show that when negotiations are purely instrumental individuals prefer pro-outgroup deviants as representatives (Experiments 1 and 2). In contrast, when negotiations are identity-related, group members increase their preference for normative (Experiments 1 and 2) and pro-ingroup deviants (Experiment 1). Furthermore, these goals also impact perceptions of typicality of group members. Taken together, these results suggest strategic acceptance of deviance when the goal is to bring the other party to concede and increased preference for normativity when identity is the group''s main preoccupation. We discuss implications of these results for research on negotiation as well as on the influence of the intergroup context on intragroup dynamics. [Copyright &y& Elsevier]

Social categorization is a powerful determinant of social behavior. As group membership becomes salient, individuals come to behave as group members and, consequently, appraise interactions according to these salient group identities (Turner, 1987). The aim of the present article is to investigate the impact of social categorization on perceptions and appraisals of a distributive negotiation situation. An experiment is presented in which social categorization of the negotiation partner is manipulated. Results revealed that the social structural factors associated with the partner’s group (i.e. social status and group’s competition) influence fixed-pie perceptions as well as participants’ inferences about their counterpart’s target and resistance points. In addition, these effects are mediated by stereotypical evaluations of the counterpart in terms of warmth and competence, respectively. [ABSTRACT FROM PUBLISHER]

Abstract: 2D-, 3D-QSAR and docking studies were carried out on 23 pyrrole derivatives, to model their HIV-1 gp41 inhibitory activities. The 2D, 3D-QSAR studies were performed using CODESSA software package and comparative molecular field analysis (CoMFA) technique, respectively. The CODESSA five-descriptor model has a correlation coefficient R 2 =0.825 and a standard deviation s 2 =0.132. The 3D-QSAR CoMFA study allowed to obtain a model showing a good correlative and predictive capability which statistical results, provided by a eight-component regression equation, are: R 2 =0.984, q 2 =0.463, s =0.119. Docking studies were employed to determine probable binding conformation of these analogues into the gp41 active site using the AutoDock program whose results were found complementary with thus of 2D- and 3D-QSAR analysis. These findings provide guidance for the design and structural modifications of these derivatives for better anti-HIV-1 activity which is important for the development of a new class of entry inhibitors. [Copyright &y& Elsevier]

Throughout adulthood, new neurons are continuously added to the dentate gyrus, a hippocampal subregion that is important in spatial learning. Whether these adult-generated granule cells become functionally integrated into memory networks is not known. We used immunohistochemical approaches to visualize the recruitment of new neurons into circuits supporting water maze memory in intact mice. We show that as new granule cells mature, they are increasingly likely to be incorporated into circuits supporting spatial memory. By the time the cells are 4 or more weeks of age, they are more likely than existing granule cells to be recruited into circuits supporting spatial memory. This preferential recruitment supports the idea that new neurons make a unique contribution to memory processing in the dentate gyrus. [ABSTRACT FROM AUTHOR]

In the era of antibiotic resistance, there is an urgent need for efficient antibiotic therapies to fight bacterial infections. Cationic antimicrobial peptides (CAMP) are promising lead compounds given their membrane-targeted mechanism of action, and high affinity towards the anionic composition of bacterial membranes. We present a new CAMP, W-BP100, derived from the highly active BP100, holding an additional tryptophan at the N-terminus. W-BP100 showed a broader antibacterial activity, demonstrating a potent activity against Gram-positive strains. Revealing a high partition constant towards anionic over zwitterionic large unilamellar vesicles and inducing membrane saturation at a high peptide/lipid ratio, W-BP100 has a preferential location for hydrophobic environments. Contrary to BP100, almost no aggregation of anionic vesicles is observed around saturation conditions and at higher concentrations no aggregation is observed. With these results, it is possible to state that with the incorporation of a single tryptophan to the N-terminus, a highly active peptide was obtained due to the π–electron system of tryptophan, resulting in negatively charged clouds, that participate in cation–π interactions with lysine residues. Furthermore, we propose that W-BP100 action can be achieved by electrostatic interactions followed by peptide translocation. [ABSTRACT FROM AUTHOR]

Although the clarity of many memories fades with time, some memories may maintain their original precision. Here we used a context discrimination procedure to evaluate whether the hippocampus is important in maintaining precision as memories mature. Spared discrimination in hippocampal-lesioned mice indicated that precise, remote context memories may be supported by extra-hippocampal brain regions. [ABSTRACT FROM AUTHOR]

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure–activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CAD related properties and was successfully challenged through strict internal and external validation procedures. The physicochemical information encoded by the identified descriptors can be used to propose specific structural modifications to design better CAD antitubercular compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: Drosophila suzukii is a major destructive insect pest with a pandemic distribution. The lack of effective green control measures for this pest has prompted the search for new approaches, among which are peptides from animal venom. In this study, the biological activity of two underexplored spider venom peptides (J-atracotoxin-Hv1c and µ-theraphotoxin-Hhn2b) was assessed against adult D. suzukii flies, as well as the biological response of flies to these peptides through detoxification mechanisms. Results demonstrate that µ-theraphotoxin-Hhn2b enhanced fly longevity. Gene expression analysis suggests that detoxification and stress-related mechanisms are triggered in D. suzukii flies in response to treatment with these peptides. Our results highlight the potential of venom peptides to control D. suzukii, underscoring the issue of how to ultimately devise improved target-specific formulations. The spotted-wing drosophila (Drosophila suzukii) is a polyphagous pest that causes severe damage and economic losses to soft-skinned fruit production. Current control methods are dominated by inefficient cultural practices and broad-spectrum insecticides that, in addition to having toxic effects on non-target organisms, are becoming less effective due to acquired resistance. The increasing awareness of the real impact of insecticides on health and the environment has promoted the exploration of new insecticidal compounds, addressing novel molecular targets. This study explores the efficacy of two orally delivered spider venom peptides (SVPs), J-atracotoxin-Hv1c (Hv1c) and µ-theraphotoxin-Hhn2b (TRTX), to manage D. suzukii, through survival assays and the evaluation of gene expression associated with detoxification pathways. Treatment with TRTX at 111.5 µM for 48 h enhanced fly longevity compared with the control group. Gene expression analysis suggests that detoxification and stress-related mechanisms, such as expression of P450 proteins and apoptotic stimuli signaling, are triggered in D. suzukii flies in response to these treatments. Our results highlight the potential interest of SVPs to control this pest, shedding light on how to ultimately develop improved target-specific formulations. [ABSTRACT FROM AUTHOR]

It is key to fight bacterial adhesion to prevent biofilm establishment on biomaterials. Surface immobilization of antimicrobial peptides (AMP) is a promising strategy to avoid bacterial colonization. This work aimed to investigate whether the direct surface immobilization of Dhvar5, an AMP with head-to-tail amphipathicity, would improve the antimicrobial activity of chitosan ultrathin coatings. The peptide was grafted by copper-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry by either its C- or N- terminus to assess the influence of peptide orientation on surface properties and antimicrobial activity. These features were compared with those of coatings fabricated using previously described Dhvar5-chitosan conjugates (immobilized in bulk). The peptide was chemoselectively immobilized onto the coating by both termini. Moreover, the covalent immobilization of Dhvar5 by either terminus enhanced the antimicrobial effect of the chitosan coating by decreasing colonization by both Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. Relevantly, the antimicrobial performance of the surface on Gram-positive bacteria depended on how Dhvar5-chitosan coatings were produced. An antiadhesive effect was observed when the peptide was grafted onto prefabricated chitosan coatings (film), and a bactericidal effect was exhibited when coatings were prepared from Dhvar5-chitosan conjugates (bulk). This antiadhesive effect was not due to changes in surface wettability or protein adsorption but rather depended on variations in peptide concentration, exposure, and surface roughness. Results reported in this study show that the antibacterial potency and effect of immobilized AMP vary greatly with the immobilization procedure. Overall, independently of the fabrication protocol and mechanism of action, Dhvar5-chitosan coatings are a promising strategy for the development of antimicrobial medical devices, either as an antiadhesive or contact-killing surface. [ABSTRACT FROM AUTHOR]

Although the hippocampus plays a crucial role in the formation of spatial memories, as these memories mature they may become additionally (or even exclusively) dependent on extrahippocampal structures. However, the identity of these extrahippocampal structures that support remote spatial memory is currently not known. Using a Morris water-maze task, we show that the anterior cingulate cortex (ACC) plays a key role in the expression of remote spatial memories in mice. To first evaluate whether the ACC is activated after the recall of spatial memory, we examined the expression of the immediate early gene, c-fos, in the ACC. Fos expression was elevated after expression of a remote (1 month old), but not recent (1 d old), water-maze memory, suggesting that ACC plays an increasingly important role as a function of time. Consistent with the gene expression data, targeted pharmacological inactivation of the ACC with the sodium channel blocker lidocaine blocked expression of remote, but spared recent, spatial memory. In contrast, inactivation of the dorsal hippocampus disrupted expression of spatial memory, regardless of its age. We further showed that inactivation of the ACC blocked expression of remote spatial memory in two different mouse strains, after training with either a hidden or visible platform in a constant location, and using the AMPA receptor antagonist CNQX. Together, our data provide evidence that circuits supporting spatial memory are reorganized in a time-dependent manner, and establish that activity in neurons intrinsic to the ACC is critical for processing remote spatial memories. [ABSTRACT FROM AUTHOR]

This work reports the synthesis, structural and thermal analysis, and in vitro evaluation of the antimicrobial activity of two new organic salts (OSs) derived from the antimycobacterial drug clofazimine and the fluoroquinolones ofloxacin or norfloxacin. Organic salts derived from active pharmaceutical ingredients (API-OSs), as those herein disclosed, hold promise as cost-effective formulations with improved features over their parent drugs, thus enabling the mitigation of some of their shortcomings. For instance, in the specific case of clofazimine, its poor solubility severely limits its bioavailability. As compared to clofazimine, the clofazimine-derived OSs now reported have improved solubility and thermostability, without any major deleterious effects on the drug's bioactivity profile. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two families of N -cinnamoyl-aminoacridine conjugates are proposed as antiproliferative leads. • One family of conjugates showed in vitro activity against three cancer cell lines in the micromolar range. • Two conjugates showed better antiproliferative activity in vitro than reference drugs. • The most promising conjugates were highly selective, showing no toxicity to non-carcinogenic cells. Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans- cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N -cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells. [ABSTRACT FROM AUTHOR]

Peptides have positively impacted the pharmaceutical industry as drugs, biomarkers, or diagnostic tools of high therapeutic value. However, only a handful have progressed to the market. Toxicity is one of the main obstacles to translating peptides into clinics. Hemolysis or hemotoxicity, the principal source of toxicity, is a natural or disease-induced event leading to the death of vital red blood cells. Initial screenings for toxicity have been widely evaluated using erythrocytes as the gold standard. More recently, many online databases filled with peptide sequences and their biological meta-data have paved the way toward hemolysis prediction using user-friendly, fast-access machine learning-driven programs. This review details the growing contributions of in silico approaches developed in the last decade for the large-scale prediction of erythrocyte lysis induced by peptides. After an overview of the pharmaceutical landscape of peptide therapeutics, we highlighted the relevance of early hemolysis studies in drug development. We emphasized the computational models and algorithms used to this end in light of historical and recent findings in this promising field. We benchmarked seven predictors using peptides from different data sets, having 7–35 amino acids in length. According to our predictions, the models have scored an accuracy over 50.42% and a minimal Matthew's correlation coefficient over 0.11. The maximum values for these statistical parameters achieved 100.0% and 1.00, respectively. Finally, strategies for optimizing peptide selectivity were described, as well as prospects for future investigations. The development of in silico predictive approaches to peptide toxicity has just started, but their important contributions clearly demonstrate their potential for peptide science and computer-aided drug design. Methodology refinement and increasing use will motivate the timely and accurate in silico identification of selective, non-toxic peptide therapeutics. [ABSTRACT FROM AUTHOR]

Emotions influence information processing because they are assumed to carry valuable information. We predict that induced anger will increase ethnic but not gender intergroup bias because anger is related to conflicts for resources, and ethnic groups typically compete for resources, whereas gender groups typically engage in relations of positive interdependence. Furthermore, we also predict that this increased ethnic intergroup bias should only be observed among men because men show more group-based reactions to intergroup conflict than women do. Two studies, with 65 and 120 participants, respectively, indeed show that anger induction increases ethnic but not gender intergroup bias and only for men. Intergroup bias was measured with an implicit measure. In Study 2, we additionally predict (and find) that fear induction does not change ethnic or gender intergroup bias because intergroup bias is a psychological preparation for collective action and fear is not associated with taking action against out-groups. We conclude that the effect of anger depends on its specific informational potential in a particular intergroup context. These results highlight that gender groups differ on a crucial point from ethnic groups and call for more attention to the effect of people's gender in intergroup relations research. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

2D and 3D QSAR studies were applied on a set of 28 diarylpyrimidine derivatives to model and understand their HIV-1 reverse transcriptase (RT) inhibitory activities. Special cares were taken to build our set of molecules according to their bioactive conformations which is crucial to elaborate good QSAR models. 2D QSAR was performed using the heuristic method in CODESSA which had led to a linear model ( R 2 = 0.928 and s 2 = 0.015) between the inhibitory activity and five descriptors. CoMFA and CoMSIA models were established using SYBYL package of programs. The better predictive ability of the CoMSIA model ( q 2 = 0.730) over the CoMFA model ( q 2 = 0.597) was assigned to the large contribution of hydrogen-bonding interactions to the inhibitory activity. CoMSIA physicochemical properties are in agreement with the 2D QSAR descriptors. The CoMSIA PLS contour surfaces were mapped to the binding pocket of the RT and showed that the results obtained by the 2D and 3D models are in respect with the protein environment. This link permitted us to validate our model and give important insights for the structure activity interpretations. These results will guide further structural modification and prediction of new HIV-1 RT inhibitors. [ABSTRACT FROM AUTHOR]

In addition to the morphophysiological changes experienced by amphibians during metamorphosis, they must also deal with a different set of environmental constraints when they shift from the water to the land. We found that Pithecopus azureus secretes a single peptide ([M + H]+ = 658.38 Da) at the developmental stage that precedes the onset of terrestrial behaviour. De novo peptide and cDNA sequencing revealed that the peptide, named PaT-2, is expressed in tandem and is a member of the tryptophyllins family. In silico studies allowed us to identify the position of reactive sites and infer possible antioxidant mechanisms of the compounds. Cell-based assays confirmed the predicted antioxidant activity in mammalian microglia and neuroblast cells. The potential neuroprotective effect of PaT-2 was further corroborated in FRET-based live cell imaging assays, where the peptide prevented lipopolysaccharide-induced ROS production and glutamate release in human microglia. In summary, PaT-2 is the first peptide expressed during the ontogeny of P. azureus, right before the metamorphosing froglet leaves the aquatic environment to occupy terrestrial habitats. The antioxidant activity of PaT-2, predicted by in silico analyses and confirmed by cell-based assays, might be relevant for the protection of the skin of P. azureus adults against increased O2 levels and UV exposure on land compared with aquatic environments. [ABSTRACT FROM AUTHOR]

[Display omitted] 4,9-diaminoacridines with reported antiplasmodial activity were coupled to different trans -cinnamic acids, delivering a new series of conjugates inspired by the covalent bitherapy concept. The new compounds were more potent than primaquine against hepatic stages of Plasmodium berghei , although this was accompanied by cytotoxic effects on Huh-7 hepatocytes. Relevantly, the conjugates displayed nanomolar activities against blood stage P. falciparum parasites, with no evidence of hemolytic effects below 100 µM. Moreover, the new compounds were at least 25-fold more potent than primaquine against P. falciparum gametocytes. Thus, the new antiplasmodial hits disclosed herein emerge as valuable templates for the development of multi-stage antiplasmodial drug candidates. [ABSTRACT FROM AUTHOR]

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons, which inhibit GCs. We used viral delivery of designer receptors exclusively activated by designer drugs (DREADDs) in mice to implement a gain- and loss-of-function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some, but not all, types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety. [ABSTRACT FROM AUTHOR]

Cruzain is an established target for the identification of novel trypanocidal agents, but how good are in vitro/in vivo correlations? This work describes the development of a random forests model for the prediction of the bioavailability of cruzain inhibitors that are Trypanosoma cruzi killers. Some common properties that characterize drug‐likeness are poorly represented in many established cruzain inhibitors. This correlates with the evidence that many high‐affinity cruzain inhibitors are not trypanocidal agents against T. cruzi. On the other hand, T. cruzi killers that present typical drug‐like characteristics are likely to show better trypanocidal action than those without such features. The random forests model was not outperformed by other machine learning methods (such as artificial neural networks and support vector machines), and it was validated with the synthesis of two new trypanocidal agents. Specifically, we report a new lead compound, Neq0565, which was tested on T. cruzi Tulahuen (β‐galactosidase) with a pEC50 of 4.9. It is inactive in the host cell line showing a selectivity index (SI = EC50cyto/EC50T. cruzi) higher than 50. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Unprecedented 9-step route towards N 4, N 9-disubstituted 4,9-diaminoacridines, starting from 4-chlorosalicylic acid. • Insertion of the N 9-substituent prior to the N 4-substituent is preferable. • Nitro-aniline reduction step could only be achieved by using SnCl 2 /aq. HCl. • Target structures combine the pharmacophores of mepacrine, chloroquine and primaquine, three classical antimalarial drugs. Abstract A multi-step synthetic route towards N 4, N 9-disubstituted 4,9-diaminoacridines that, to the best of our knowledge, has no precedence in the literature, has been developed. The target structures are likely to reveal interesting biological activities in the near future, not only due to their mepacrine-like core, but also because they embed simultaneously the pharmacophores of chloroquine and primaquine, antimalarial drugs that act at different stages of malaria infection. [ABSTRACT FROM AUTHOR]

The emergence of antibiotic resistance drives an essential race against time to reveal new molecular structures capable of addressing this alarming global health problem. Snake venoms are natural catalogs of multifunctional toxins and privileged frameworks, which serve as potential templates for the inspiration of novel treatment strategies for combating antibiotic resistant bacteria. Phospholipases A2 (PLA2s) are one of the main classes of antibacterial biomolecules, with recognized therapeutic value, found in these valuable secretions. Recently, a number of biomimetic oligopeptides based on small fragments of primary structure from PLA2 toxins has emerged as a meaningful opportunity to overcome multidrug‐resistant clinical isolates. Thus, this review will highlight the biochemical and structural properties of antibacterial PLA2s and peptides thereof, as well as their possible molecular mechanisms of action and key roles in development of effective therapeutic strategies. Chemical strategies possibly useful to convert antibacterial peptides from PLA2s to efficient drugs will be equally addressed. [ABSTRACT FROM AUTHOR]

Agricultural systems are in need of low-cost, safe antibiotics to protect crops from pests and diseases. Peptaibiotics, a family of linear, membrane-active, amphipathic polypeptides, have been shown to exhibit antibacterial, antifungal, and antiviral activity, and to be inducers of plant resistance against a wide range of phytopathogens. Peptaibiotics belong to the new generation of alternatives to agrochemicals, aligned with the United Nations Sustainable Development Goals and the One Health approach toward ensuring global food security and safety. Despite that, these fungi-derived, non-ribosomal peptides remain surprisingly understudied, especially in agriculture, where only a small number has been tested against a reduced number of phytopathogens. This lack of adoption stems from peptaibiotics' poor water solubility and the difficulty to synthesize and purify them in vitro , which compromises their delivery and inclusion in formulations. In this review, we offer a comprehensive analysis of peptaibiotics' classification, biosynthesis, relevance to plant protection, and mode of action against phytopathogens, along with the techniques enabling researchers to extract, purify, and elucidate their structure, and the databases holding such valuable data. It is also discussed how chemical synthesis and ionic liquids could increase their solubility, how genetic engineering and epigenetics could boost in vitro production, and how omics can reduce screenings' workload through in silico selection of the best candidates. These strategies could turn peptaibiotics into effective, ultra-specific, biodegradable tools for phytopathogen control. • Peptaibiotics' are bioactive against a wide range of phytopathogens. • Peptaibiotics' poor water solubility compromises their delivery and inclusion in formulations. • Novel techniques, like chemical synthesis and ionic liquids, could increase their solubility. • Genetic engineering and epigenetics could boost peptaibiotics' in vitro production. • Omics can reduce screenings' workload through in silico genome mining selection of best isolate and molecule. [ABSTRACT FROM AUTHOR]

A novel family of 4-aminoacridine derivatives was obtained by linking this heteroaromatic core to different trans -cinnamic acids. The 4-(N -cinnamoylbutyl)aminoacridines obtained exhibited in vitro activity in the low- or sub-micromolar range against (i) hepatic stages of Plasmodium berghei , (ii) erythrocytic forms of Plasmodium falciparum , and (iii) early and mature gametocytes of Plasmodium falciparum. The most active compound, having a meta -fluorocinnamoyl group linked to the acridine core, was 20- and 120-fold more potent, respectively, against the hepatic and gametocyte stages of Plasmodium infection than the reference drug, primaquine. Moreover, no cytotoxicity towards mammalian and red blood cells at the concentrations tested was observed for any of the compounds under investigation. These novel conjugates represent promising leads for the development of new multi-target antiplasmodials. [Display omitted] • 4-(N -cinnamoylbutyl)aminoacridines were synthesized as potential multi-stage antiplasmodial leads. • Hybrids were active against blood-, liver- and gametocyte-stages of Plasmodium. • The most active compound contained a meta -fluorocinnamoyl group linked to the acridine core. • None of the derivatives were toxic against red blood cells at the highest concentration tested. [ABSTRACT FROM AUTHOR]

Malaria, leishmaniasis and Chagas disease are vector-borne protozoal infections with a disproportionately high impact on the most fragile societies in the world, and despite malaria-focused research gained momentum in the past two decades, both trypanosomiases and leishmaniases remain neglected tropical diseases. Affordable effective drugs remain the mainstay of tackling this burden, but toxicicty, inneficiency against later stage disease, and drug resistance issues are serious shortcomings. One strategy to overcome these hurdles is to get new therapeutics or inspiration in nature. Indeed, snake venoms have been recognized as valuable sources of biomacromolecules, like peptides and proteins, with antiprotozoal activity. This review highlights major snake venom components active against at least one of the three aforementioned diseases, which include phospholipases A2, metalloproteases, L-amino acid oxidases, lectins, and oligopeptides. The relevance of this repertoire of biomacromolecules and the bottlenecks in their clinical translation are discussed considering approaches that should increase the success rate in this arduous task. Overall, this review underlines how venom-derived biomacromolecules could lead to pioneering antiprotozoal treatments and how the drug landscape for neglected diseases may be revolutionized by a closer look at venoms. Further investigations on poorly studied venoms is needed and could add new therapeutics to the pipeline. [Display omitted] [ABSTRACT FROM AUTHOR]