Low potency toxins reveal dense interaction networks in metabolism

Background The chemicals of metabolism are constructed of a small set of atoms and bonds. This may be because chemical structures outside the chemical space in which life operates are incompatible with biochemistry, or because mechanisms to make or utilize such excluded structures has not evolved. In this paper I address the extent to which biochemistry is restricted to a small fraction of the chemical space of possible chemicals, a restricted subset that I call Biochemical Space. I explore evidence that this restriction is at least in part due to selection again specific structures, and suggest a mechanism by which this occurs. Results Chemicals that contain structures that our outside Biochemical Space (UnBiological groups) are more likely to be toxic to a wide range of organisms, even though they have no specifically toxic groups and no obvious mechanism of toxicity. This correlation of UnBiological with toxicity is stronger for low potency (millimolar) toxins. I relate this to the observation that most chemicals interact with many biological structures at low millimolar toxicity. I hypothesise that life has to select its components not only to have a specific set of functions but also to avoid interactions with all the other components of life that might degrade their function. Conclusions The chemistry of life has to form a dense, self-consistent network of chemical structures, and cannot easily be arbitrarily extended. The toxicity of arbitrary chemicals is a reflection of the disruption to that network occasioned by trying to insert a chemical into it without also selecting all the other components to tolerate that chemical. This suggests new ways to test for the toxicity of chemicals, and that engineering organisms to make high concentrations of materials such as chemical precursors or fuels may require more substantial engineering than just of the synthetic pathways involved

Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets

Human-mediated biological exchange has had global social and ecological impacts. In subS-aharan Africa, several domestic and commensal animals were introduced from Asia in the pre-modern period; however, the timing and nature of these introductions remain contentious. One model supports introduction to the eastern African coast after the mid-first millennium CE, while another posits introduction dating back to 3000 BCE. These distinct scenarios have implications for understanding the emergence of long-distance maritime connectivity, and the ecological and economic impacts of introduced species. Resolution of this longstanding debate requires new efforts, given the lack of well-dated fauna from high-precision excavations, and ambiguous osteomorphological identifications. We analysed faunal remains from 22 eastern African sites spanning a wide geographic and chronological range, and applied biomolecular techniques to confirm identifications of two Asian taxa: domestic chicken (Gallus gallus) and black rat (Rattus rattus). Our approach included ancient DNA (aDNA) analysis aided by BLAST-based bioinformatics, Zooarchaeology by Mass Spectrometry (ZooMS) collagen fingerprinting, and direct AMS (accelerator mass spectrometry) radiocarbon dating. Our results support a late, mid-first millennium CE introduction of these species. We discuss the implications of our findings for models of biological exchange, and emphasize the applicability of our approach to tropical areas with poor bone preservation

Nuclear Factor (NF) κB polymorphism is associated with heart function in patients with heart failure

<p>Abstract</p> <p>Background</p> <p>Cardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the <it>NFKB1 </it>gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.</p> <p>Methods</p> <p>A total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.</p> <p>Results</p> <p>We did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG₁/ATTG₁genotype with right ventricle diameter (<it>P </it>= 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG₁/ATTG₁more frequent in patients with EF lower than 50% (<it>P </it>= 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG₁carriers.</p> <p>Conclusion</p> <p>There is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of <it>NFKB1</it>, previously associated with the ATTG₁/ATTG₁genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.</p

Community-based distributive medical education: Advantaging society

This paper presents a narrative summary of an increasingly important trend in medical education by addressing the merits of community-based distributive medical education (CBDME). This is a relatively new and compelling model for teaching and training physicians in a manner that may better meet societal needs and expectations. Issues and trends regarding the growing shortage and imbalanced distribution of physicians in the USA are addressed, including the role of international medical graduates. A historical overview of costs and funding sources for medical education is presented, as well as initiatives to increase the training and placement of physicians cost-effectively through new and expanded medical schools, two- and four-year regional or branch campuses and CBDME. Our research confirms that although medical schools have responded to Association of American Medical Colleges calls for higher student enrollment and societal concerns about the distribution and placement of physicians, significant opportunities for improvement remain. Finally, the authors recommend further research be conducted to guide policy on incentives for physicians to locate in underserved communities, and determine the cost-effectiveness of the CBDME model in both the near and long terms

Identification and comparative analysis of components from the signal recognition particle in protozoa and fungi

BACKGROUND: The signal recognition particle (SRP) is a ribonucleoprotein complex responsible for targeting proteins to the ER membrane. The SRP of metazoans is well characterized and composed of an RNA molecule and six polypeptides. The particle is organized into the S and Alu domains. The Alu domain has a translational arrest function and consists of the SRP9 and SRP14 proteins bound to the terminal regions of the SRP RNA. So far, our understanding of the SRP and its evolution in lower eukaryotes such as protozoa and yeasts has been limited. However, genome sequences of such organisms have recently become available, and we have now analyzed this information with respect to genes encoding SRP components. RESULTS: A number of SRP RNA and SRP protein genes were identified by an analysis of genomes of protozoa and fungi. The sequences and secondary structures of the Alu portion of the RNA were found to be highly variable. Furthermore, proteins SRP9/14 appeared to be absent in certain species. Comparative analysis of the SRP RNAs from different Saccharomyces species resulted in models which contain features shared between all SRP RNAs, but also a new secondary structure element in SRP RNA helix 5. Protein SRP21, previously thought to be present only in Saccharomyces, was shown to be a constituent of additional fungal genomes. Furthermore, SRP21 was found to be related to metazoan and plant SRP9, suggesting that the two proteins are functionally related. CONCLUSIONS: Analysis of a number of not previously annotated SRP components show that the SRP Alu domain is subject to a more rapid evolution than the other parts of the molecule. For instance, the RNA portion is highly variable and the protein SRP9 seems to have evolved into the SRP21 protein in fungi. In addition, we identified a secondary structure element in the Sacccharomyces RNA that has been inserted close to the Alu region. Together, these results provide important clues as to the structure, function and evolution of SRP

Functional polymorphism of the NFKB1 gene promoter is related to the risk of dilated cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Previous studies in experimental and human heart failure showed that nuclear factor kappa B (NF-κB) is chronically activated in cardiac myocytes, suggesting an important involvement of NF-κB in the cardiac remodeling process. A common insertion/deletion (-94 insertion/deletion ATTG, rs28362491) located between two putative key promoter regulatory elements in the <it>NFKB1 </it>gene was identified which seems to be the first potential functional <it>NFKB1 </it>genetic variation. The main goal of the present investigation was to investigate the <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism in relation to risk of dilated cardiomyopathy (DCM).</p> <p>Methods</p> <p>A total of 177 DCM patients and 203 control subjects were successfully investigated. The <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism was genotyped by using PCR-PAGE.</p> <p>Results</p> <p>Genotype frequency of <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism in DCM patients was significantly different from that in control subjects (<it>P </it>= 0.015) and the ATTG₂carrier (ATTG₁/ATTG₂+ ATTG₂/ATTG₂) was susceptible to DCM.</p> <p>Conclusion</p> <p>Our data suggested that <it>NFKB1 </it>-94 insertion/deletion ATTG polymorphism is associated with DCM.</p

Controlled Chaos of Polymorphic Mucins in a Metazoan Parasite (Schistosoma mansoni) Interacting with Its Invertebrate Host (Biomphalaria glabrata)

Invertebrates were long thought to possess only a simple, effective and hence non-adaptive defence system against microbial and parasitic attacks. However, recent studies have shown that invertebrate immunity also relies on immune receptors that diversify (e.g. in echinoderms, insects and mollusks (Biomphalaria glabrata)). Apparently, individual or population-based polymorphism-generating mechanisms exists that permit the survival of invertebrate species exposed to parasites. Consequently, the generally accepted arms race hypothesis predicts that molecular diversity and polymorphism also exist in parasites of invertebrates. We investigated the diversity and polymorphism of parasite molecules (Schistosoma mansoni Polymorphic Mucins, SmPoMucs) that are key factors for the compatibility of schistosomes interacting with their host, the mollusc Biomphalaria glabrata. We have elucidated the complex cascade of mechanisms acting both at the genomic level and during expression that confer polymorphism to SmPoMuc. We show that SmPoMuc is coded by a multi-gene family whose members frequently recombine. We show that these genes are transcribed in an individual-specific manner, and that for each gene, multiple splice variants exist. Finally, we reveal the impact of this polymorphism on the SmPoMuc glycosylation status. Our data support the view that S. mansoni has evolved a complex hierarchical system that efficiently generates a high degree of polymorphism—a “controlled chaos”—based on a relatively low number of genes. This contrasts with protozoan parasites that generate antigenic variation from large sets of genes such as Trypanosoma cruzi, Trypanosoma brucei and Plasmodium falciparum. Our data support the view that the interaction between parasites and their invertebrate hosts are far more complex than previously thought. While most studies in this matter have focused on invertebrate host diversification, we clearly show that diversifying mechanisms also exist on the parasite side of the interaction. Our findings shed new light on how and why invertebrate immunity develops

Multi-Target Drugs: The Trend of Drug Research and Development

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target–target and drug–drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future

MicroRNA Involvement in Immune Activation During Heart Failure

Heart failure is one of the common end stages of cardiovascular diseases, the leading cause of death in developed countries. Molecular mechanisms underlying the development of heart failure remain elusive but there is a consistent observation of chronic immune activation and aberrant microRNA (miRNA) expression that is present in failing hearts. This review will focus on the interplay between the immune system and miRNAs as factors that play a role during the development of heart failure. Several studies have shown that heart failure patients can be characterized by a sustained innate immune activation. The role of inflammatory signaling is discussed and TLR4 signaling, IL-1β, TNFα and IL-6 expression appears to coincide with the development of heart failure. Furthermore, we describe the implication of the renin angiotensin aldosteron system in immunity and heart failure. In the past decade microRNAs (miRNAs), small non-coding RNAs that translationally repress protein synthesis by binding to partially complementary sequences of mRNA, have come to light as important regulators of several kinds of cardiovascular diseases including cardiac hypertrophy and heart failure. The involvement of differentially expressed miRNAs in the inflammation that occurs during the development of heart failure is still subject of investigation. Here, we summarize and comment on the first studies in this field and hypothesize on the putative involvement of certain miRNAs in heart failure. MicroRNAs have been shown to be critical regulators of cardiac function and inflammation. Future research will have to point out if dampening the immune response, and the miRNAs associated with it, during the development of heart failure is a therapeutically plausible route to follow

Human and Non-Human Primate Genomes Share Hotspots of Positive Selection

Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs) in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution