In insect societies, chemical communication plays an important role in colony reproduction and individual social status. Many studies have indicated that cuticular hydrocarbons (CHCs) are the main ...chemical compounds encoding reproductive status. However, these studies have largely focused on queenless or monogynous species whose workers are capable of egg laying and have mainly explored the mechanisms underlying queen-worker or worker-worker reproductive conflicts. Less is known about what occurs in highly polygynous ant species with permanently sterile workers. Here, we used the Argentine ant as a model to examine the role of CHCs in communicating reproductive information in such insect societies. The Argentine ant is unicolonial, highly polygynous, and polydomous. We identified several CHCs whose presence and levels were correlated with queen age, reproductive status, and fertility. Our results also provide new insights into queen executions in the Argentine ant, a distinctive feature displayed by this species in its introduced range. Each spring, just before new sexuals appear, workers eliminate up to 90% of the mated queens in their colonies. We discovered that queens that survived execution had different CHC profiles from queens present before and during execution. More specifically, levels of some CHCs were higher in the survivors, suggesting that workers could eliminate queens based on their chemical profiles. In addition, queen CHC profiles differed based on season and species range (native vs. introduced). Overall, the results of this study provide new evidence that CHCs serve as queen signals and do more than just regulate worker reproduction.
Genital warts are a common and highly contagious sexually transmitted disease. They have a large economic burden and affect several aspects of quality of life. Incidence data underestimate the real ...occurrence of genital warts because this infection is often under-reported, mostly due to their specific characteristics such as the asymptomatic course.
Genital warts cases for the analysis were obtained from the Catalan public health system database (SIDIAP) for the period 2009-2016. People under 15 and over 94 years old were excluded from the analysis as the incidence of genital warts in this population is negligible. This work introduces a time series model based on a mixture of two distributions, capable of detecting the presence of under-reporting in the data. In order to identify potential differences in the magnitude of the under-reporting issue depending on sex and age, these covariates were included in the model.
This work shows that only about 80% in average of genital warts incidence in Catalunya in the period 2009-2016 was registered, although the frequency of under-reporting has been decreasing over the study period. It can also be seen that this issue has a deeper impact on women over 30 years old.
Although this study shows that the quality of the registered data has improved over the considered period of time, the Catalan public health system is underestimating genital warts real burden in almost 10,000 cases, around 23% of the registered cases. The total annual cost is underestimated in about 10 million Euros respect the 54 million Euros annually devoted to genital warts in Catalunya, representing 0.4% of the total budget.
Cerebrospinal fluid (CSF) is the fluid of choice to study pathologies and disorders of the central nervous system (CNS). Its composition, especially its proteins and peptides, holds the promise that ...it may reflect the pathological state of an individual. Traditionally, proteins and peptides in CSF have been analyzed using bottom-up proteomics technologies in the search of high proteome coverage. However, the limited protein sequence coverage of this technology means that information regarding post-translational modifications (PTMs) and alternative splice variants is lost. As an alternative technology, top-down proteomics offers low to medium proteome coverage, but high protein coverage enabling almost a full characterization of the proteins' primary structure. This allows us to precisely identify distinct molecular forms of proteins (proteoforms) as well as naturally occurring bioactive peptide fragments, which could be of critical biological relevance and would otherwise remain undetected with a classical proteomics approach.Here, we describe various strategies including sample preparation protocols, off-line intact protein prefractionation, and LC-MS/MS methods together with data analysis pipelines to analyze cerebrospinal fluid (CSF) by top-down proteomics. However, there is not a unique or standardized method and the selection of the top-down strategy will depend on the exact goal of the study. Here, we describe various top-down proteomics methods that enable rapid protein characterization and may be an excellent companion analytical workflow in the search for new protein biomarkers in neurodegenerative diseases.
Glycogen synthase (GS) and glycogen phosphorylase (GP) are the key enzymes that control, respectively, the synthesis and degradation of glycogen, a multi-branched glucose polymer that serves as a ...form of energy storage in bacteria, fungi and animals. An abnormal glycogen metabolism is associated with several human diseases. Thus, GS and GP constitute adequate pharmacological targets to modulate cellular glycogen levels by means of their selective inhibition. The compound 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) is a known potent inhibitor of GP. We studied the inhibitory effect of DAB, its enantiomer LAB, and 29 DAB derivatives on the activity of rat muscle glycogen phosphorylase (RMGP) and E. coli glycogen synthase (EcGS). The isoform 4 of sucrose synthase (SuSy4) from Solanum tuberosum L. was also included in the study for comparative purposes. Although these three enzymes possess highly conserved catalytic site architectures, the DAB derivatives analysed showed extremely diverse inhibitory potential. Subtle changes in the positions of crucial residues in their active sites are sufficient to discriminate among the structural differences of the tested inhibitors. For the two Leloir-type enzymes, EcGS and SuSy4, which use sugar nucleotides as donors, the inhibitory potency of the compounds analysed was synergistically enhanced by more than three orders of magnitude in the presence of ADP and UDP, respectively. Our results are consistent with a model in which these compounds bind to the subsite in the active centre of the enzymes that is normally occupied by the glucosyl residue which is transferred between donor and acceptor substrates. The ability to selectively inhibit the catalytic activity of the key enzymes of the glycogen metabolism may represent a new approach for the treatment of disorders of the glycogen metabolism.
Year 2000 estimates of the incidence of cancer indicate that primary liver cancer remains the fifth most common malignancy in men and the eighth in women. The number of new cases has been predicted ...as 564,000, corresponding to 398,000 in men and 166,000 in women. The geographic areas at highest risk are located in Eastern Asia, Middle Africa, and some countries of Western Africa. Changes in incidence among migrant populations underline the predominant role of environmental factors in the etiology of primary liver cancer. In high-risk countries, the early cases of primary liver cancer occur already at ages 20 and above, underlying the impact of viral exposures early in life. In countries at low risk, primary liver cancer is rare before the 50s, translating the impact of late exposures with moderate risks and long latency intervals. Sex ratios are typically between 2 and 4. The incidence of primary liver cancer is increasing in several developed countries including the United States, and the increase will likely continue for several decades. The trend has a dominant cohort effect related to exposures to hepatitis B and C viruses. The variability of primary liver cancer incidence is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.
Abstract
Background
Most cost-effectiveness analyses in the context of cervical cancer prevention involve the use of mathematical models to simulate HPV infection, cervical disease and prevention ...strategies. However, it is common for professionals who would need to perform these analyses to not be familiar with the models. This work introduces the
Online Cost-Effectiveness ANalysis
tool, featuring an easy-to-use web interface providing health professionals, researchers and decision makers involved in cervical cancer prevention programmes with a useful instrument to conduct complex cost-effectiveness analyses, which are becoming an essential tool as an approach for supporting decision-making that involves important trade-offs.
Results
The users can run cost-effectiveness evaluations of cervical cancer prevention strategies without deep knowledge of the underlying mathematical model or any programming language, obtaining the most relevant costs and health outcomes in a user-friendly format. The results provided by the tool are consistent with the existing literature.
Conclusions
Having such a tool will be an asset to the cervical cancer prevention community, providing researchers with an easy-to-use instrument to conduct cost-effectiveness analyses.
The multifunctional character of tryptophan has made it a target for the development of new molecules with therapeutic applications. In this sense the design of alternative solid phase routes would ...allow the widening of synthetic possibilities to access these molecules through conventional or combinatorial strategies. The present work describes a new strategy for side-chain anchoring of tryptophan to dihydropyranyl-functionalized polystyrene resins and its application to the synthesis of the natural diketopiperazine Brevianamide F. For this study a new handle (4-(3,4-dihydro-2
H
-pyran-2-yl)methoxybenzoic acid) was prepared in order to functionalize aminomethyl or methylbenzhydrylamine resins. A preliminary study in solution using Fmoc-Trp-OR (R = Allyl or Me) and suitable resin models showed that the formation of an hemiaminal linkage with the indole system could be brought about by either conventional or microwave heating in 1,2-dichloroethane and in the presence of pyridine
p
-toluenesulfonate in yields of 70–95% practically without the formation of sub-products. On the other hand the amino acid could be liberated from the resin at room temperature in yields of up to 90% using trifluoroacetic acid in dichloromethane in the presence of 1,3-dimethoxybenzene as a cation scavenger. The conditions found in solution for the reversible formation of the hemiaminal were only reproducible in solid-phase work using conventional heating. These conditions were used in the synthesis of Brevianamide F, furnishing the diketopiperazine in an overall yield of 56%. These results demonstrate the potential of this strategy for the preparation of new molecules based upon tryptophan as a synthetic precursor.
Geschwindigkeit ist alles: Damit ein Azofarbstoff für die Echtzeit‐Datenübermittlung geeignet ist, muss er nach Photoisomerisierung in seine metastabile cis‐Form eine schnelle thermische ...Isomerisierung zurück zur trans‐Form eingehen. Das gezeigte Azopyrimidin hat eine Relaxationszeit τ von nur 40 ns unter physiologischen Bedingungen und ist hoch biokompatibel, wie durch das Wachstum von Escherichia coli in seiner Gegenwart belegt wird (siehe Bild).
In contrast to the well-studied canonical regulatory mechanisms, the way by which the recently discovered Src N-terminal regulatory element (SNRE) modulates Src activity is not yet well understood. ...Phosphorylation of serine and threonine residues modulates the charge distribution along the disordered region of the SNRE and may affect a fuzzy complex with the SH3 domain that is believed to act as an information transduction element. The pre-existing positively charged sites can interact with the newly introduced phosphate groups by modulating their acidity, introducing local conformational restrictions, or by coupling various phosphosites into a functional unit. In this paper, we use pH-dependent NMR measurements combined with single point mutations to identify the interactions of basic residues with physiologically important phosphorylated residues and to characterize the effect of these interactions in neighbor residues, thus providing insight into the electrostatic network in the isolated disordered regions and in the entire SNRE. From a methodological point of view, the linear relationships observed between the mutation-induced pKa changes of the phosphate groups of phosphoserine and phosphothreonine and the pH-induced chemical shifts of the NH groups of these residues provide a very convenient alternative to identify interacting phosphate groups without the need to introduce point mutations on specific basic residues.
Decarboxylation of malonyl-CoA to acetyl-CoA by malonyl-CoA decarboxylase (MCD; EC 4.1.1.9) is an essential facet in the regulation of fatty acid metabolism. The structure of human peroxisomal MCD ...reveals a molecular tetramer that is best described as a dimer of structural heterodimers, in which the two subunits present markedly different conformations. This molecular organization is consistent with half-of-the-sites reactivity. Each subunit has an all-helix N-terminal domain and a catalytic C-terminal domain with an acetyltransferase fold (GNAT superfamily). Intersubunit disulfide bridges, Cys-206–Cys-206 and Cys-243–Cys-243, can link the four subunits of the tetramer, imparting positive cooperativity to the catalytic process. The combination of a half-of-the-sites mechanism within each structural heterodimer and positive cooperativity in the tetramer produces a complex regulatory picture that is further complicated by the multiple intracellular locations of the enzyme. Transport into the peroxisome has been investigated by docking human MCD onto the peroxisomal import protein peroxin 5, which revealed interactions that extend beyond the C-terminal targeting motif.
Background: Malonyl-CoA, a key molecule playing central roles in fatty acids metabolism, is associated with human diseases such as malonic aciduria.
Results: Crystal structures and functional data were determined for human malonyl-CoA decarboxylase (MCD), responsible for malonyl-CoA decarboxylation.
Conclusion: MCD catalytic activity combines half-of-the-sites reactivity with positive cooperativity modulated by intersubunit disulfide bridges.
Significance: Structural and functional information on MCD provides elements for a better understanding of the associated pathologies.
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