“One-Size-Fits-All”? Optimizing Treatment Duration for Bacterial Infections

Historically, antibiotic treatment guidelines have aimed to maximize treatment efficacy and minimize toxicity, but have not considered the evolution of antibiotic resistance. Optimizing the duration and dosing of treatment to minimize the duration of symptomatic infection and selection pressure for resistance simultaneously has the potential to extend the useful therapeutic life of these valuable life-saving drugs without compromising the interests of individual patients

Agrin Binds BMP2, BMP4 and TGFβ1

The C-terminal 95 kDa fragment of some isoforms of vertebrate agrins is sufficient to induce clustering of acetylcholine receptors but despite two decades of intense agrin research very little is known about the function of the other isoforms and the function of the larger, N-terminal part of agrins that is common to all isoforms. Since the N-terminal part of agrins contains several follistatin-domains, a domain type that is frequently implicated in binding TGFβs, we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFβ family using surface plasmon resonance spectroscopy and reporter assays. Here we show that agrin binds BMP2, BMP4 and TGFβ1 with relatively high affinity, the KD values of the interactions calculated from SPR experiments fall in the 10−8 M–10−7 M range. In reporter assays Agrin-Nterm inhibited the activities of BMP2 and BMP4, half maximal inhibition being achieved at ∼5×10−7 M. Paradoxically, in the case of TGFβ1 Agrin N-term caused a slight increase in activity in reporter assays. Our finding that agrin binds members of the TGFβ family may have important implications for the role of these growth factors in the regulation of synaptogenesis as well as for the role of agrin isoforms that are unable to induce clustering of acetylcholine receptors. We suggest that binding of these TGFβ family members to agrin may have a dual function: agrin may serve as a reservoir for these growth factors and may also inhibit their growth promoting activity. Based on analysis of the evolutionary history of agrin we suggest that agrin's growth factor binding function is more ancient than its involvement in acetylcholine receptor clustering

Metabolic Profiles and cDNA-AFLP Analysis of Salvia miltiorrhiza and Salvia castanea Diel f. tomentosa Stib

Plants of the genus Salvia produce various types of phenolic compounds and tanshinones which are effective for treatment of coronary heart disease. Salvia miltiorrhiza and S. castanea Diels f. tomentosa Stib are two important members of the genus. In this study, metabolic profiles and cDNA-AFLP analysis of four samples were employed to identify novel genes potentially involved in phenolic compounds and tanshinones biosynthesis, including the red roots from the two species and two tanshinone-free roots from S. miltiorrhiza. The results showed that the red roots of S. castanea Diels f. tomentosa Stib produced high contents of rosmarinic acid (21.77 mg/g) and tanshinone IIA (12.60 mg/g), but low content of salvianolic acid B (1.45 mg/g). The red roots of S. miltiorrhiza produced high content of salvianolic acid B (18.69 mg/g), while tanshinones accumulation in this sample was much less than that in S. castanea Diels f. tomentosa Stib. Tanshinones were not detected in the two tanshinone-free samples, which produced high contents of phenolic compounds. A cDNA-AFLP analysis with 128 primer pairs revealed that 2300 transcript derived fragments (TDFs) were differentially expressed among the four samples. About 323 TDFs were sequenced, of which 78 TDFs were annotated with known functions through BLASTX searching the Genbank database and 14 annotated TDFs were assigned into secondary metabolic pathways through searching the KEGGPATHWAY database. The quantitative real-time PCR analysis indicated that the expression of 9 TDFs was positively correlated with accumulation of phenolic compounds and tanshinones. These TDFs additionally showed coordinated transcriptional response with 6 previously-identified genes involved in biosynthesis of tanshinones and phenolic compounds in S. miltiorrhiza hairy roots treated with yeast extract. The sequence data in the present work not only provided us candidate genes involved in phenolic compounds and tanshinones biosynthesis but also gave us further insight into secondary metabolism in Salvia

C. elegans Agrin Is Expressed in Pharynx, IL1 Neurons and Distal Tip Cells and Does Not Genetically Interact with Genes Involved in Synaptogenesis or Muscle Function

Agrin is a basement membrane protein crucial for development and maintenance of the neuromuscular junction in vertebrates. The C. elegans genome harbors a putative agrin gene agr-1. We have cloned the corresponding cDNA to determine the primary structure of the protein and expressed its recombinant fragments to raise specific antibodies. The domain organization of AGR-1 is very similar to the vertebrate orthologues. C. elegans agrin contains a signal sequence for secretion, seven follistatin domains, three EGF-like repeats and two laminin G domains. AGR-1 loss of function mutants did not exhibit any overt phenotypes and did not acquire resistance to the acetylcholine receptor agonist levamisole. Furthermore, crossing them with various mutants for components of the dystrophin-glycoprotein complex with impaired muscle function did not lead to an aggravation of the phenotypes. Promoter-GFP translational fusion as well as immunostaining of worms revealed expression of agrin in buccal epithelium and the protein deposition in the basal lamina of the pharynx. Furthermore, dorsal and ventral IL1 head neurons and distal tip cells of the gonad arms are sources of agrin production, but no expression was detectable in body muscles or in the motoneurons innervating them. Recombinant worm AGR-1 fragment is able to cluster vertebrate dystroglycan in cultured cells, implying a conservation of this interaction, but since neither of these proteins is expressed in muscle of C. elegans, this interaction may be required in different tissues. The connections between muscle cells and the basement membrane, as well as neuromuscular junctions, are structurally distinct between vertebrates and nematodes

Aloe barbadensis: how a miraculous plant becomes reality

Aloe barbadensis Miller is a plant that is native to North and East Africa and has accompanied man for over 5,000 years. The aloe vera plant has been endowed with digestive, dermatological, culinary and cosmetic virtues. On this basis, aloe provides a range of possibilities for fascinating studies from several points of view, including the analysis of chemical composition, the biochemistry involved in various activities and its application in pharmacology, as well as from horticultural and economic standpoints. The use of aloe vera as a medicinal plant is mentioned in numerous ancient texts such as the Bible. This multitude of medicinal uses has been described and discussed for centuries, thus transforming this miracle plant into reality. A summary of the historical uses, chemical composition and biological activities of this species is presented in this review. The latest clinical studies involved in vivo and in vitro assays conducted with aloe vera gel or its metabolites and the results of these studies are reviewed

Inapproximability of the independent set polynomial in the complex plane

We study the complexity of approximating the value of the independent set polynomial ZG(λ) of a graph G with maximum degree Δ when the activity λ is a complex number. When λ is real, the complexity picture is well-understood, and is captured by two real-valued thresholds λ* and λc, which depend on Δ and satisfy 0<λ*<λc. It is known that if λ is a real number in the interval (−λ*,λc) then there is an FPTAS for approximating ZG(λ) on graphs G with maximum degree at most Δ. On the other hand, if λ is a real number outside of the (closed) interval, then approximation is NP-hard. The key to establishing this picture was the interpretation of the thresholds λ* and λc on the Δ-regular tree. The ”occupation ratio” of a Δ-regular tree T is the contribution to ZT(λ) from independent sets containing the root of the tree, divided by ZT(λ) itself. This occupation ratio converges to a limit, as the height of the tree grows, if and only if λ∈ [−λ*,λc]. Unsurprisingly, the case where λ is complex is more challenging. It is known that there is an FPTAS when λ is a complex number with norm at most λ* and also when λ is in a small strip surrounding the real interval [0,λc). However, neither of these results is believed to fully capture the truth about when approximation is possible. Peters and Regts identified the values of λ for which the occupation ratio of the Δ-regular tree converges. These values carve a cardioid-shaped region ΛΔ in the complex plane, whose boundary includes the critical points −λ* and λc. Motivated by the picture in the real case, they asked whether ΛΔ marks the true approximability threshold for general complex values λ. Our main result shows that for every λ outside of ΛΔ, the problem of approximating ZG(λ) on graphs G with maximum degree at most Δ is indeed NP-hard. In fact, when λ is outside of ΛΔ and is not a positive real number, we give the stronger result that approximating ZG(λ) is actually #P-hard. Further, on the negative real axis, when λ0, resolving in the affirmative a conjecture of Harvey, Srivastava and Vondrak. Our proof techniques are based around tools from complex analysis — specifically the study of iterative multivariate rational maps

Inapproximability of the independent set polynomial in the complex plane

We study the complexity of approximating the value of the independent set polynomial ZG(λ) of a graph G with maximum degree Δ when the activity λ is a complex number. When λ is real, the complexity picture is well-understood, and is captured by two real-valued thresholds λ* and λc, which depend on Δ and satisfy 0&lt;λ*&lt;λc. It is known that if λ is a real number in the interval (−λ*,λc) then there is an FPTAS for approximating ZG(λ) on graphs G with maximum degree at most Δ. On the other hand, if λ is a real number outside of the (closed) interval, then approximation is NP-hard. The key to establishing this picture was the interpretation of the thresholds λ* and λc on the Δ-regular tree. The ”occupation ratio” of a Δ-regular tree T is the contribution to ZT(λ) from independent sets containing the root of the tree, divided by ZT(λ) itself. This occupation ratio converges to a limit, as the height of the tree grows, if and only if λ∈ [−λ*,λc]. Unsurprisingly, the case where λ is complex is more challenging. It is known that there is an FPTAS when λ is a complex number with norm at most λ* and also when λ is in a small strip surrounding the real interval [0,λc). However, neither of these results is believed to fully capture the truth about when approximation is possible. Peters and Regts identified the values of λ for which the occupation ratio of the Δ-regular tree converges. These values carve a cardioid-shaped region ΛΔ in the complex plane, whose boundary includes the critical points −λ* and λc. Motivated by the picture in the real case, they asked whether ΛΔ marks the true approximability threshold for general complex values λ. Our main result shows that for every λ outside of ΛΔ, the problem of approximating ZG(λ) on graphs G with maximum degree at most Δ is indeed NP-hard. In fact, when λ is outside of ΛΔ and is not a positive real number, we give the stronger result that approximating ZG(λ) is actually #P-hard. Further, on the negative real axis, when λ&lt;−λ*, we show that it is #P-hard to even decide whether ZG(λ)&gt;0, resolving in the affirmative a conjecture of Harvey, Srivastava and Vondrak. Our proof techniques are based around tools from complex analysis — specifically the study of iterative multivariate rational maps

The complexity of approximating the matching polynomial in the complex plane

We study the problem of approximating the value of the matching polynomial on graphs with edge parameter γ, where γ takes arbitrary values in the complex plane. When γ is a positive real, Jerrum and Sinclair showed that the problem admits an FPRAS on general graphs. For general complex values of γ, Patel and Regts, building on methods developed by Barvinok, showed that the problem admits an FPTAS on graphs of maximum degree Δ as long as γ is not a negative real number less than or equal to −1/(4(Δ −1)). Our first main result completes the picture for the approximability of the matching polynomial on bounded degree graphs. We show that for all Δ ≥ 3 and all real γ less than −1/(4(Δ −1)), the problem of approximating the value of the matching polynomial on graphs of maximum degree Δ with edge parameter γ is #P-hard. We then explore whether the maximum degree parameter can be replaced by the connective constant. Sinclair et al. showed that for positive real γ, it is possible to approximate the value of the matching polynomial using a correlation decay algorithm on graphs with bounded connective constant (and potentially unbounded maximum degree). We first show that this result does not extend in general in the complex plane; in particular, the problem is #P-hard on graphs with bounded connective constant for a dense set of γ values on the negative real axis. Nevertheless, we show that the result does extend for any complex value γ that does not lie on the negative real axis. Our analysis accounts for complex values of γ using geodesic distances in the complex plane in the metric defined by an appropriate density function