Novel pharmacological actions of Trequinsin Hydrochloride improve human sperm cell motility and function

Background and purposeAsthenozoospermia is a leading cause of male infertility, but the development of pharmaceuticals to improve sperm motility has been hindered by the lack of effective screening platforms and knowledge of suitable molecular targets. We have demonstrated that a high throughput screening (HTS) strategy in conjunction with established in vitro tests can identify and characterise the action of compounds that improve sperm motility. The study aimed to apply HTS to identify new compounds from a novel small molecule library that increase intracellular calcium, [Ca2+]I, promote human sperm cell motility and systemically determine the mechanism of action. Experimental approach A validated HTS fluorometric [Ca2+]i assay was used to screen an in-house library of compounds. Trequinsin hydrochloride (a phosphodiesterase 3 inhibitor) was selected for detailed molecular (plate reader assays, electrophysiology and cyclic nucleotide measurement) and functional (motility and acrosome reaction) testing in sperm from healthy volunteer donors and, where possible, patients.   Key resultsThe fluorometric analysis identified Trequinsin as an efficacious agonist of [Ca2+]i, although less potent than progesterone (P4). Functionally, Trequinsin significantly increased cell hyperactivation and penetration into viscous medium in all donor sperm samples and cell hyperactivation in 22/25 (88%) patient sperm samples. The Trequinsin-induced [Ca2+]i response was cross-desensitised consistently by prostaglandin E1 but not with P4. Whole-cell patch clamp electrophysiology confirmed that Trequinsin activates CatSper and partially inhibits potassium channel activity. Trequinsin also increases intracellular cGMP.   Conclusion and Implications Trequinsin exhibits a novel pharmacological profile in human sperm and may be a suitable lead compound for the development of new pharmaceuticals to improve patient sperm function and fertilisation potential

The trade off between diversity and quality for multi-objective workforce scheduling

In this paper we investigate and compare multi-objective and weighted single objective approaches to a real world workforce scheduling problem. For this difficult problem we consider the trade off in solution quality versus population diversity, for different sets of fixed objective weights. Our real-world workforce scheduling problem consists of assigning resources with the appropriate skills to geographically dispersed task locations while satisfying time window constraints. The problem is NP-Hard and contains the Resource Constrained Project Scheduling Problem (RCPSP) as a sub problem. We investigate a genetic algorithm and serial schedule generation scheme together with various multi-objective approaches. We show that multi-objective genetic algorithms can create solutions whose fitness is within 2% of genetic algorithms using weighted sum objectives even though the multi-objective approaches know nothing of the weights. The result is highly significant for complex real-world problems where objective weights are seldom known in advance since it suggests that a multi-objective approach can generate a solution close to the user preferred one without having knowledge of user preferences

Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

Flavor Changing Neutral Currents involving Heavy Quarks with Four Generations

We study various FCNC involving heavy quarks in the Standard Model (SM) with a sequential fourth generation. After imposing $B\to X_s\gamma$, $B\to X_sl^+l^-$ and $Z\to b\bar{b}$ constraints, we find ${\cal B}(Z\to s\bar{b}+\bar{s}b)$ can be enhanced by an order of magnitude to $10^{-7}$, while $t\to cZ, cH$ decays can reach $10^{-6}$, which are orders of magnitude higher than in SM. However,these rates are still not observable for the near future.With the era of LHC approaching, we focus on FCNC decays involving fourth generation $b^\prime$ and $t^\prime$ quarks. We calculate the rates for loop induced FCNC decays $b^\prime\to bZ, bH, bg, b\gamma$, as well as t^\prime\to tZ,\tH, tg, t\gamma. If $|V_{cb'}|$ is of order $|V_{cb}| \simeq 0.04$, tree level $b^\prime\to cW$ decay would dominate, posing a challenge since $b$-tagging is less effective. For $|V_{cb'}| \ll |V_{cb}|$, $b'\to tW$ would tend to dominate, while $b'\to t^\prime W^*$ could also open for heavier $b'$, leading to thepossibility of quadruple-$W$ signals via $b'\bar b'\to b\bar b W^+W^-W^+W^-$. The FCNC $b'\to bZ, bH$ decays could still dominate if $m_{b'}$ is just above 200 GeV. For the case of $t'$, ingeneral $t^\prime\to bW$ would be dominant, hence it behaves like a heavy top. For both $b'$ and $t'$, except for the intriguing light $b'$ case, FCNC decays are in the $10^{-4} -10^{-2}$ range, and are quite detectable at the LHC.For a possible future ILC, we find the associated production of FCNC $e^+e^-\to b\bar s$, $t\bar c$ are below sensitivity, while $e^+e^-\to b^\prime\bar b$ and$t^\prime\bar t$ can be better probed.Tevatron Run-II can still probe the lighter $b'$ or $t'$ scenario. LHC would either discover the fourth generation and measure the FCNC rates, or rule out the fourth generation conclusively.Comment: 31 pages, 15 eps figures, version to appear in JHE

Exciton Spin Dynamics in Semiconductor Quantum Wells

In this paper we will review Exciton Spin Dynamics in Semiconductor Quantum Wells. The spin properties of excitons in nanostructures are determined by their fine structure. We will mainly focus in this review on GaAs and InGaAs quantum wells which are model systems.Comment: 55 pages, 27 figure

Fitomassa de adubos verdes e controle de plantas daninhas em diferentes densidades populacionias de leguminosas.

O objetivo deste trabalho foi avaliar a fitomassa de calopogônio, mucuna-preta, mucunarajada,feijão-de-porco, guandu de porte alto, Crotalaria spectabilis e C. breviflora sob diferentes densidades de semeadura (10, 20, 40, 80 e 160 sementes viáveis m-2), e o crescimento de plantas daninhas nessas densidades, em área de tabuleiros costeiros. O experimento foi desenvolvido de maio a agosto de 1996, no Campo Experimental “Antônio Martins”(EMDAGRO/Embrapa-CPATC), em Lagarto, SE. O número de plantas vivas na floração (NPVF) e a matéria seca da parte aérea das leguminosas (MSPA) foram determinados quando, em cada espécie, cerca de 50% das plantas floresceram. Maiores incrementos de MSPA, em resposta ao adensamento populacional, foram observados em C. spectabilis e C. breviflora, seguidas pelo calopogônio, mucuna-preta e mucuna-rajada. Em relação ao feijão-de-porco, a resposta foi negativa, enquanto com o guandu não houve influência. Quanto ao NPVF, as respostas ao adensamento foram lineares e positivas em C. spectabilis, C. breviflora e calopogônio, e quadráticas com ponto de máxima em feijão-de-porco,guandu e mucuna-rajada. Embora nenhum modelo tenha sido ajustado para expressar a relação entre NPVF e adensamento na semeadura de mucuna-preta, a sobrevivência dessa espécie foi reduzida em todas as densidades. Maiores inibições de plantas daninhas ocorreram nas parcelas de mucuna-preta e feijão-de-porco

The role of secreted aspartyl proteinases in Candida tropicalis invasion and damage of oral mucosa

Candida virulence attributes include the ability to colonize and invade host tissues, and the secretion of hydrolytic enzymes. Although Candida albicans is regarded as the principal fungi causing infections in humans, other species, particularly Candida tropicalis, are increasingly being recognized as human pathogens. Relatively little is known, however, about the virulence attributes associated with C. tropicalis. The present study aimed to investigate epithelial infection by C. tropicalis using a reconstituted human oral epithelium (RHOE) together with confocal laser scanning microscopy and real-time PCR. A comparison of clinical strains was made in terms of tissue colonization, invasion and C. tropicalis secreted aspartyl proteinase (SAPT) gene expression. All C. tropicalis strains were able to colonize RHOE in a strain-dependent manner. After 12 h of infection, C. tropicalis was found to be highly invasive, with extensive tissue damage occurring after 24 h. Real-time PCR of C. tropicalis SAPT1-4 genes showed that expression was strain-dependent, with SAPT2-4 transcripts being frequently detected and SAPT1 rarely detected. Tissue invasion and damage was not inhibited by the presence of pepstatin A. Accordingly, and given that an increase in infection time was not accompanied with an increase in SAPT gene expression, it can be suggested that the proteinases are not involved in invasion and damage of RHOE by C. tropicalis. In summary, C. tropicalis can be considered as highly invasive with the ability to induce significant tissue damage. These features, however, do not appear to be related to specific SAPT gene expression.We would like to thank Mrs Kath Allsopp for processing and sectioning the tissue samples. This work was supported by grant SFRH/BD/28341/2006 from 'Fundacao para a Ciencia e Tecnologia' (FCT), Portugal

Constraints on the Nucleon Strange Form Factors at Q^2 ~ 0.1 GeV^2

We report the most precise measurement to date of a parity-violating asymmetry in elastic electron-proton scattering. The measurement was carried out with a beam energy of 3.03 GeV and a scattering angle =6 degrees, with the result A_PV = -1.14 +/- 0.24 (stat) +/- 0.06 (syst) parts per million. From this we extract, at Q^2 = 0.099 GeV^2, the strange form factor combination G_E^s + 0.080 G_M^s = 0.030 +/- 0.025 (stat) +/- 0.006 (syst) +/- 0.012 (FF) where the first two errors are experimental and the last error is due to the uncertainty in the neutron electromagnetic form factor. This result significantly improves current knowledge of G_E^s and G_M^s at Q^2 ~0.1 GeV^2. A consistent picture emerges when several measurements at about the same Q^2 value are combined: G_E^s is consistent with zero while G_M^s prefers positive values though G_E^s=G_M^s=0 is compatible with the data at 95% C.L.Comment: minor wording changes for clarity, updated references, dropped one figure to improve focu