When shared concept cells support associations: Theory of overlapping memory engrams

Assemblies of neurons, called concepts cells, encode acquired concepts in human Medial Temporal Lobe. Those concept cells that are shared between two assemblies have been hypothesized to encode associations between concepts. Here we test this hypothesis in a computational model of attractor neural networks. We find that for concepts encoded in sparse neural assemblies there is a minimal fraction c_min of neurons shared between assemblies below which associations cannot be reliably implemented; and a maximal fraction c_max of shared neurons above which single concepts can no longer be retrieved. In the presence of a periodically modulated background signal, such as hippocampal oscillations, recall takes the form of association chains reminiscent of those postulated by theories of free recall of words. Predictions of an iterative overlap-generating model match experimental data on the number of concepts to which a neuron responds.     

Vine Deloria Jr. as a Philosopher of Education: An Essay of Remembrance

This essay engages the concepts of maturity, relationality, and responsibility in the writings of Vine Deloria Jr. as foundational to a Native philosophy of education. After situating Deloria and these Native philosophic concepts as a moment of difference in the colonial—modern world, I explore how these concepts of maturity, relationships, and responsibility have been discussed in his work and remain potent forces in the continuing evolution of education among Native peoples.     

Pattern, process and the evolution of meaning: species and units of selection

Many of the fundamental concepts of biology lack consensual, precise definitions. Partly, this is due to a contrast between our discrete language and the continuous character of nature. Some debates over these concepts are confounded by the use of the same terms with different specific meanings, indicating a possible need for an expanded scientific lexicon. Words have their own histories, and frequently scientific terms with a vernacular origin retain associated vestigial meanings. Even terms newly coined within science have histories and changing meanings, which can lead to confusion among debaters. Debates over concepts are further confounded when the same terms are used in different fields of biology, with distinct (even conflicting) objectives, and by biologists with different approaches and perspectives. I illustrate these issues by considering the debate over the concept of species and the unit of selection.     

Synthesis and biological evaluation of the metabolites of 2-(1-{3-[(6-chloronaphthalen-2-yl)sulfonyl]propanoyl}piperidin-4-yl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one

We have recently discovered imidazo[1,5-c]imidazol-3-one derivative 1 as a potent, selective, and orally bioavailable factor Xa (FXa) inhibitor. In this study, we have synthesized metabolites of 1 and evaluated their biological activities. As a result, we identified the active metabolites S-5 and 6 with a potent FXa inhibitory activity comparable to 1 and a favorable pharmacokinetic profile in monkeys.     

Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.     

Comparative metabolomic study between African and Amazonian Symphonia globulifera by tandem LC–HRMS

According to the literature, the phytochemistry of Symphonia globulifera (Clusiacea) seems to be highly correlated to the local ecosystem. None of the already isolated 31 metabolites from Africa were common with the 13 isolated in French Guiana. Considering the potent therapeutic activities of these metabolites, we have investigated these differences thought a LC–HRMSⁿ conducted metabolomic approach. By using a database correlation and fragmentation patterns, 37 compounds responsible of the variation have been putatively annotated. Among these metabolites, only 6 were already described in this species. This study highlights the relatively restrict phytochemical knowledge of Symphonia globulifera, a species with potent therapeutic metabolites and thus, allow faster phytochemical mapping for further isolation.     

Design,synthesis and biological evaluation of new inhibitors of Bax/Bcl-xL interaction in cancer cells

We describe the synthesis of a series of new molecules containing phenol and triazoles moieties, compounds which have been evaluated for their ability to inhibit Bax/Bcl-xL interactions in cancer cells, by using BRET assays, and to induce cell death. Several derivatives exhibit a very promising activity, being more potent than the reference compounds acylpyrogallol A and ABT-737. These preliminary results demonstrate that derivatives of this family can be attractive to develop new molecules with potent anticancer activity.     

Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

Screening of a pteridine-based compound library led to the identification of compounds exhibiting immunosuppressive as well as anti-inflammatory activity. Optimization afforded a series of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)pteridine analogues. The most potent congeners in this series displayed low nM IC₅₀ values in the Mixed Lymphocyte Reaction (MLR) assay. In addition, these compounds also have potent anti-inflammatory activity as measured in the Tumor Necrosis Factor (TNF) assay.     

Why are some numerical concepts more successful than others? An evolutionary perspective on the history of number concepts

From the history of mathematics, it is clear that some numerical concepts are far more pervasive than others. In a densely multimodular mind, evolved cognitive abilities lie at the basis of human culture and cognition. One possible way to explain the differential spread and survival of cultural concepts based on this assumption is the epidemiology of culture. This approach explains the relative success of cultural concepts as a function of their fit with intuitions provided by conceptual modules. A wealth of recent evidence from animal, infant, and neuroimaging studies suggests that human numerical competence is rooted in an evolved number module. In this study, I adopted an epidemiological perspective to examine the cultural transmission of numerical concepts in the history of mathematics. Drawing on historical and anthropological data on number concepts, I will demonstrate that positive integers, zero, and negative numbers have divergent cultural evolutionary histories owing to a distinct relationship with the number module. These case studies provide evidence for the claim that science can be explained in terms of evolved cognitive abilities that are universal in Homo sapiens.     

Is otolith science transformative? New views on fish migration

Publications focused on fish otolith applications grew exponentially from 1981–2000 but have subsequently stabilized, suggesting maturation of otolith applications. Over the past 30 years >3,500 primary journal publications were identified prompting the question, how have otoliths fundamentally changed our understanding of fishes and their environment? Has otolith science in this way been transformative? I use Harden Jones’ 1968 Fish Migration as a benchmark of fish migration concepts prior to Pannella’s 1971 breakthrough paper on otolith microstructure. For case study species I highlight how otolith science has informed migration concepts including, (1) parent stream theory (Atlantic bluefin tuna), (2) adoptive homing (Atlantic herring), and (3) partial migration (European eel). Harden Jones’ overall conclusion that life cycle closure leads to population structure (also known as the migration triangle) is a first principle in fisheries science, but in recent years has been challenged by otolith science. In particular, a transformative discovery attributable to otoliths is that life cycles vary substantially within populations. New avenues of otolith science are now exploring the causes and consequences of this life cycle diversity, and large advances are expected through integration of otolith approaches with electronic tagging, genetics, field manipulations, and modeling that will permit migration concepts to be tested at multiple ecological scales.     

Generic names in the Orbiliaceae (Orbiliomycetes) and recommendations on which names should be protected or suppressed

A list of all generic names that have been connected with the Orbiliomycetes is provided. Recommendations are made as to which names should be used in accordance with the rules and the different generic concepts. There is a mismatch in the current generic concepts within Orbiliomycetes regarding the two morphs: a narrow concept is used for the asexual morphs, but a broad concept relies on the sexual morphs. As a consequence, many more generic names have been established for the asexual morphs. A number of previous generic concepts are artificial, since they were based on single characters without molecular support. In order to provide solutions for this mismatch, we present three different generic concepts within the Orbiliomycetes. A broad concept recognizes a large genus Orbilia, with which most of the listed names fall into synonymy, but could be maintained as infrageneric names. Due to the lack of data proving phylogenetic relationships, this broad concept, at present, is the most practicable and recommended one. A moderate concept subdivides Orbilia into several genera, with all nematode-trapping fungi merged in Arthrobotrys. A narrow generic concept accepts genera based on differences in trapping organs, but also subdivides the remaining groups of Orbilia into additional genera. Trapping of invertebrates (zoophagy) is not restricted to Arthrobotrys in a broad sense, but occurs also in the more distant basal genera Hyalorbilia and Lecophagus, which mainly prey on rhizopods and rotifers. Whether these predatory capabilities trace back to a common ancestor is not clear. The following new combinations are proposed: Hyalorbilia oviparasitica, Hyalorbilia quadridens, Hyalorbilia tenuifusaria, and Orbilia fissilis.     

Antineoplastic kinase inhibitors: A new class of potent anti-amoebic compounds

Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, a long treatment course, and the need for an additional drug to prevent cyst-mediated transmission. E. histolytica possesses a kinome with approximately 300–400 members, some of which have been previously studied as potential targets for the development of amoebicidal drug candidates. However, while these efforts have uncovered novel potent inhibitors of E. histolytica kinases, none have resulted in approved drugs. In this study we took the alternative approach of testing a set of twelve previously FDA-approved antineoplastic kinase inhibitors against E. histolytica trophozoites in vitro. This resulted in the identification of dasatinib, bosutinib, and ibrutinib as amoebicidal agents at low-micromolar concentrations. Next, we utilized a recently developed computational tool to identify twelve additional drugs with human protein target profiles similar to the three initial hits. Testing of these additional twelve drugs led to the identification of ponatinib, neratinib, and olmutinib were identified as highly potent, with EC₅₀ values in the sub-micromolar range. All of these six drugs were found to kill E. histolytica trophozoites as rapidly as metronidazole. Furthermore, ibrutinib was found to kill the transmissible cyst stage of the model organism E. invadens. Ibrutinib thus possesses both amoebicidal and cysticidal properties, in contrast to all drugs used in the current therapeutic strategy. These findings together reveal antineoplastic kinase inhibitors as a highly promising class of potent drugs against this widespread and devastating disease.     

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.     

Reviewing once more the c-myc and Ras collaboration: Converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology

The c-myc is a proto-oncogene that manifests aberrant expression at high frequencies in most types of human cancer. C-myc gene amplifications are often observed in various cancers as well. Ample studies have also proved that c-myc has a potent oncogenicity, which can be further enhanced by collaborations with other oncogenes such as Bcl-2 and activated Ras. Studies on the collaborations of c-myc with Ras or other genes in oncogenicity have established several basic concepts and have disclosed their underlying mechanisms of tumor biology, including “immortalization” and “transformation”. In many cases, these collaborations may converge at the cyclin D1-CDK4 complex. In the meantime, however, many results from studies on the c-myc, Ras and cyclin D1-CDK4 also challenge these basic concepts of tumor biology and suggest to us that the immortalized status of cells should be emphasized. Stricter criteria and definitions for a malignantly transformed status and a benign status of cells in culture also need to be established to facilitate our study of the mechanisms for tumor formation and to better link up in vitro data with animal results and eventually with human cancer pathology.Key words: c-Myc, Cyclin D1, transformation, immortalization, oncogeneC-myc is the first proto-oncogene discovered and is known to participate in many cellular functions,¹ including maintenance of stem cell properties.² Most types of human cancer manifest aberrant expression of c-myc at high frequencies, and gene amplification occurs in many cases of various cancers as well. Ample studies have demonstrated that c-myc has a potent oncogenicity, which can be further enhanced by collaborations with other oncogenes such as a Ras mutant or with many extracellular growth stimuli that activate Ras, such as epidermal growth factor (EGF) or transforming growth factor α (TGFα). Studies on the collaborations of c-myc with Ras and other genes have provided us with mechanistic details behind several basic concepts of cancer biology, including the “two-hit principle”,³ “immortalization” and “transformation”. In the meantime, however, many results from these studies also challenge these basic concepts and thus confuse us. We now discuss the data on the collaborations of c-myc with Ras and other genes and present a perspective that these collaborations may converge at the cyclin D1-CDK4 complex. We also appeal to emphasize the importance of an immortalized status of cells and to establish stricter criteria to better define a transformed and benign statuses, so as to better connect in vitro results with animal data and with human cancer pathology.     

Highly-potent,synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms

The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C, and A3H) and four double deaminase domain A3s (A3B, A3D, A3F, and A3G). The most potent of the A3 proteins against HIV-1 is A3G. However, it is not clear if double deaminase domain A3s have a generalized functional advantage to restrict HIV-1. In order to test whether superior restriction factors could be created by genetically linking single A3 domains into synthetic double domains, we linked A3C and A3H single domains in novel combinations. We found that A3C/A3H double domains acquired enhanced antiviral activity that is at least as potent, if not better than, A3G. Although these synthetic double domain A3s package into budding virions more efficiently than their respective single domains, this does not fully explain their gain of antiviral potency. The antiviral activity is conferred both by cytidine-deaminase dependent and independent mechanisms, with the latter correlating to an increase in RNA binding affinity. T cell lines expressing this A3C-A3H super restriction factor are able to control replicating HIV-1ΔVif infection to similar levels as A3G. Together, these data show that novel combinations of A3 domains are capable of gaining potent antiviral activity to levels similar to the most potent genome-encoded A3s, via a primarily non-catalytic mechanism.     

Behavioral effects of the novel tropane analog, 2β-propanoyl-3β-(4-toluyl)-tropane (PTT)

In vitro studies have demonstrated that a novel tropane analog, PTT, in which both of the esters of cocaine have been removed is 20 times more potent than cocaine and more selective than cocaine in binding to dopamine transporters. The present studies compared the ability of PTT and cocaine to stimulate locomotor activity in rats. The intraperitoneal administration of PTT and cocaine to male Fisher-344 rats produced dose-dependent increases in spontaneous locomotor activity and stereotypic behaviors. PTT was 10–20 times more potent than cocaine in this behavioral assay, closely paralleling its potency relative to cocaine in dopamine transporter binding and uptake assays in vitro. PTT, however, elicited a qualitatively different profile of stereotypic behaviors, and PTT had a longer duration of action than cocaine. These results show how changes in kinetics and selectivity of tropanes can affect stimulant-elicited behaviors.     

The virally encoded killer proteins from Ustilago maydis

Several strains of Ustilago maydis, a causal agent of corn smut disease, exhibit a ‘killer’ phenotype that is due to persistent infection by double-stranded RNA Totiviruses. These viruses produce potent killer proteins that are secreted by the host. This is a rare example of virus/host symbiosis in that these viruses are dependent upon host survival and, to that end, produce antifungal proteins that kill competing, uninfected strains of U. maydis. Two of the best-studied examples of this killer phenomenon are U. maydis strains P4 and P6 that secrete killer proteins KP4 and KP6, respectively. The mature form of KP4 is comprised of 105 residues while KP6 consists of two subunits, a and b chains, 76 and 82 residues in length, respectively. KP6 is not homologous to any known protein, and only recently has KP4 been shown to have possible homologs in pathogenic fungi. While very little is known as to the mode of action of KP6, we have shown that KP4 blocks L-type Ca²⁺ channels in fungi and animal cells in a reversible and cytostatic manner. In contrast, preliminary results suggest that KP6 acts via a completely different mechanism and is a potent cytolytic antifungal protein. When KP4 is expressed in maize, the resulting transgenic lines are nearly immune to U. maydis infection. Therefore, a greater understanding of the modes of action of these potent antifungal proteins could lead to development of broad-spectrum antifungal agents.     

Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties

In oncology, the “Warburg effect” describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.     

Understanding the fate of peroxynitrite in plant cells--from physiology to pathophysiology

Peroxynitrite (ONOO⁻) is a potent oxidant and nitrating species, generated by the reaction of nitric oxide and superoxide in one of the most rapid reactions known in biology. It is widely accepted that an enhanced ONOO⁻ formation contributes to oxidative and nitrosative stress in various biological systems. However, an increasing number of studies have reported that ONOO⁻ cannot only be considered as a mediator of cellular dysfunction, but also behaves as a potent modulator of the redox regulation in various cell signal transduction pathways.Although the formation of ONOO⁻ has been demonstrated in vivo in plant cells, the relevance of this molecule during plant physiological responses is still far from being clarified. Admittedly, the detection of protein tyrosine nitration phenomena provides some justification to the speculations that ONOO is generated during various plant stress responses associated with pathophysiological mechanisms. On the other hand, it was found that ONOO⁻ itself is not as toxic for plant cells as it is for animal ones. Based on the concepts of the role played by ONOO⁻ in biological systems, this review is focused mainly on the search for potential functions of ONOO⁻ in plants. Moreover, it is also an attempt to stimulate a discussion on the significance of protein nitration as a paradigm in signal modulation, since the newest reports identified proteins associated with signal transduction cascades within the plant nitroproteome.     

Novel isoniazid embedded triazole derivatives: Synthesis,antitubercular and antimicrobial activity evaluation

In the present study, a series of new isoniazid embedded triazole derivatives have been synthesized. These compounds were evaluated for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, six have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 0.78 μg/mL, whereas, three compounds have displayed activity with MIC value ranging from 1.56 to 3.125 μg/mL. The cytotoxicity of the active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed even at 25 μg/mL concentration. The five compounds have displayed good antimicrobial activities. Molecular docking have been performed against mycobacterial InhA enzyme to gain an insight into the plausible mechanism of action which could pave the way for our endeavor to identify potent antitubercular candidates. We believe that further optimization of these molecules may lead to potent antitubercular agents.