Novel sulfur and selenium containing bis-α-amino acids from 4-hydroxyproline

The synthesis of new substituted prolines carrying at C-4 a second α-amino acid residue is reported. The amino acid, l-cysteine or l-selenocysteine, is linked to the proline ring through the sulfur or the selenium atom, respectively. The products were prepared with different stereochemistry at C-4, in few and clean high-yielding steps, with suitable protections for solid phase applications. The introduction of both sulfur and selenium atoms at C-4 of the proline ring seems to enhance significantly the cis geometry at the prolyl amide bond

HNRNPM guides an alternative splicing program in response to inhibition of the PI3K/AKT/mTOR pathway in Ewing sarcoma cells

Ewing sarcomas (ES) are biologically aggressive tumors of bone and soft tissues for which no cure is currently available. Most ES patients do not respond to chemotherapeutic treatments or acquire resistance. Since the PI3K/AKT/mTOR axis is often deregulated in ES, its inhibition offers therapeutic perspective for these aggressive tumors. Herein, by using splicing sensitive arrays, we have uncovered an extensive splicing program activated upon inhibition of the PI3K/AKT/mTOR signaling pathway by BEZ235. Bioinformatics analyses identified hnRNPM as a key factor in this response. HnRNPMmotifswere significantly enriched in introns flanking the regulated exons and proximity of binding represented a key determinant for hnRNPM-dependent splicing regulation. Knockdown of hnRNPM expression abolished a subset of BEZ235-induced splicing changes that contained hnRNPM binding sites, enhanced BEZ235 cytotoxicity and limited the clonogenicity of ES cells. Importantly, hnRNPM up-regulation correlates with poor outcome in sarcoma patients. These findings uncover an hnRNPM-dependent alternative splicing program set in motion by inhibition of the mTOR/AKT/PI3K pathway in ES cells that limits therapeutic efficacy of pharmacologic inhibitors, suggesting that combined inhibition of the PI3K/AKT/mTOR pathway and hnRNPM activity may represent a novel approach for ES treatment

Reduction and reconstruction of stochastic differential equations via symmetries

An algorithmic method to exploit a general class of infinitesimal symmetries for reducing stochastic differential equations is presented and a natural definition of reconstruction, inspired by the classical reconstruction by quadratures, is proposed. As a side result the well-known solution formula for linear one-dimensional stochastic differential equations is obtained within this symmetry approach. The complete procedure is applied to several examples with both theoretical and applied relevance

Dopaminergic and glutamatergic signaling crosstalk in Huntington's disease neurodegeneration : the role of p25/cyclin-dependent kinase 5

Altered glutamatergic and dopaminergic signaling has been proposed as contributing to the specific striatal cell death observed in Huntington's disease (HD). However, the precise mechanisms by which mutant huntingtin sensitize striatal cells to dopamine and glutamate inputs remain unclear. Here, we demonstrate in knock-in HD striatal cells that mutant huntingtin enhances dopaminemediated striatal cell death via dopamineD1 receptors. Moreover, we show thatNMDAreceptors specifically potentiate the vulnerability of mutant huntingtin striatal cells to dopamine toxicity as pretreatment withNMDAincreased D1R-induced cell death in mutant but not wild-type cells. As potential underlying mechanism of increased striatal vulnerability, we identified aberrant cyclin-dependent kinase 5 (Cdk5) activation. We demonstrate that enhanced Cdk5 phosphorylation and increased calpain-mediated conversion of the Cdk5 activator p35 into p25 may account for the deregulation of Cdk5 associated to dopamine and glutamate receptor activation in knock-in HD striatal cells. Moreover, supporting a detrimental role of Cdk5 in striatal cell death, neuronal loss can be widely prevented by roscovitine, a potent Cdk5 inhibitor. Significantly, reduced Cdk5 expression together with enhanced Cdk5 phosphorylation and p25 accumulation also occurs in the striatum of mutant HdhQ111 mice and HD human brain suggesting the relevance of deregulated Cdk5 pathway in HD pathology. These findings provide new insights into the molecular mechanisms underlying the selective vulnerability of striatal cells in HD and identify p25/Cdk5 as an important mediator of dopamine and glutamate neurotoxicity associated to HD

Diversity in nutrient content and consumer preferences of sensory attributes of peanut (Arachis hypogaea L.) varieties in Ugandan agroecosystems

The cultivated peanut (Arachis hypogaea L.) is one of the most widely consumed legumes globally due to its nutrient content, taste, and affordability. Nutrient composition and consumer preference were determined for twenty local farmer (landrace) and commercial peanut varieties grown in the Nakaseke and Nakasongola districts of the central wooded savanna of Uganda through sensory and laboratory evaluation. Significant differences in nutrient content (p < 0.05) among peanut varieties were found within and across sites. A significant relationship between nutrient content and consumer preference for varieties within and across sites was also realized (Wilk’s lambda = 0.05, p = 0.00). The differences in nutrient content influenced key organoleptic characteristics, including taste, crunchiness, appearance, and soup aroma, which contributed to why consumers may prefer certain varieties to others. Gender differences in variety selection were significantly related to consumer preference for the crunchiness of roasted peanut varieties (F = 5.7, p = 0.016). The results imply that selecting different varieties of peanuts enables consumers to receive different nutrient amounts, while experiencing variety uniqueness. The promotion of peanut intraspecific diversity is crucial for improved nutrition, organoleptic appreciation and the livelihood of those engaged in peanut value chains, especially for the actors who specialize in different peanut products. The conservation of peanut diversity will ensure that the present and future generations benefit from the nutritional content and organoleptic enjoyment that is linked to unique peanut varieties

Heterogeneity in Nutritional and Biochemical Composition of Cassava Varieties in Uganda

Cassava (Manihot esculenta Crantz) has been prioritized by the New Partnership for African Development to spur development in Africa. However, the nutritional and biochemical composition of the cassava diversity has not been adequately assessed to inform the various user needs.  Comparative analysis of macro, micro nutrients and biochemical composition of sixteen varieties of cassava in Uganda was undertaken following standard analytical techniques. Results showed significant differences in macro nutrients (p ≤0.000)  except carbohydrate, starch and amylose contents. With the exception of Calcium and Iron, the varieties were significantly different (p ≤0.000) in micronutrient composition.  The Cyanide and dry matter content were also significantly different (p ≤0.000) among the varieties. Overall, Mukibi, Juguja, Bao, Nigeria,  ranked highest in dry matter, cyanide, macro and micronutrients content, respectively. Therefore varieties differ in nutritional and biochemical composition; information crucial in the development of new varieities and deployment of cassava diversity in various  value chains

Discrete-event simulation to reduce waiting time in accident and emergency departments: a case study in a district general clinic

Waiting time is a crucial performance metric in A&E departments. In this regard, longer waiting times are related to low patient satisfaction, high mortality rates and more severe physical health complications. To analyze patient flow in these departments, discrete-event simulation (DES) has been used; however, its application has not been extended to evaluate the impact of improvement strategies. Therefore, this paper aims to design and pretest operational strategies for better ED care delivery using DES. First, input data analysis is carried out. Afterward, the DES model is developed and validated to establish whether it is statistically comparable with the real-world. Then, performance indicators of the current system are computed and analyzed. Finally, improvement strategies are proposed and evaluated by simulation modelling and statistical tests. A case study of an A&E department from a district general clinic is presented to validate the proposed framework. In particular, we will validate the effectiveness of introducing a triage system (Scenario 3), a strategy that is not currently adopted by the clinic. Results demonstrate that waiting times could be meaningfully diminished based on the proposed approaches within this paper

On the scattering amplitude in the Aharonov-Bohm gauge field

A general expression for the scattering amplitude of nonrelativistic spinless particles in the Aharonov-Bohm gauge potential is obtained within the time independent formalism. The result is valid also in the backward and forward directions as well as for any choice of the boundary conditions on the wave function at the flux tube position.Comment: 18 pages, plain TE