Conformational analysis of potent sweet taste ligands by nuclear magnetic resonance, computer simulations and X-ray diffraction studies

Four potent sweet-tasting molecules, N-(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methylester 1 (7000 times more potent than sucrose), N-(3,3-dimethylbutyl)-L-aspartyl-D-valine (S)-alpha-ethylbenzylamide 2 (3000 time more potent than sucrose), L-aspartyl-D-valine (R)-alpha-methoxymethylbenzylamide 3 (1350 times more potent than sucrose and L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide 4 (2500 times more potent than sucrose) were studied by 1H NMR and computer simulations. These flexible molecules adopt multiple conformations in solution. The "L-shaped" structure, which we believe to be responsible for sweet taste is accessible to all four compounds in solution. Extended conformations with the AH and B-containing moieties in the +y-axis and the hydrophobic group X pointing in the y-axis have also been observed for all four sweeteners. For compounds 1 and 3, the solid-state conformations were determined by X-ray diffraction studies. These results demonstrate that compounds 1 and 3 adopt an "L-shaped" structure even in the crystalline state. The extraordinary potency of the N-alkylated compound 1 compared with the unsubstituted Asp-Phe-OMe may be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the "L-shaped" structure.     

Parental criticism and externalizing behavior problems in adolescents: The role of environment and genotype–environment correlation.

Genetic factors are important for the association between parental negativity and child problem behavior, but it is not clear whether this is due to passive or evocative genotype–environment correlation (rGE). In this study, we applied the extended children-of-twins model to directly examine the presence of passive and evocative rGE as well as direct environmental effects in the association between parental criticism and adolescent externalizing problem behavior. The cross-sectional data come from the Twin and Offspring Study in Sweden (N = 909 pairs of adult twins) and from the Twin Study of Child and Adolescent Development (N = 915 pairs of twin children). The results revealed that maternal criticism was primarily due to evocative rGE emanating from their adolescent's externalizing behavior. On the other hand, fathers' critical remarks tended to affect adolescent problem behavior in a direct environmental way. This suggests that previously reported differences in caretaking between mothers and fathers also are reflected in differences in why parenting is associated with externalizing behavior in offspring. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Current Knowledge on the Pathophysiology of Lean/Normal-Weight Type 2 Diabetes

Since early times, being overweight and obesity have been associated with impaired glucose metabolism and type 2 diabetes (T2D). Similarly, a less frequent adult-onset diabetes in low body mass index (BMI) people has been known for many decades. This form is mainly found in developing countries, whereby the largest increase in diabetes incidence is expected in coming years. The number of non-obese patients with T2D is also on the rise among non-white ethnic minorities living in high-income Western countries due to growing migratory flows. A great deal of energy has been spent on understanding the mechanisms that bind obesity to T2D. Conversely, the pathophysiologic features and factors driving the risk of T2D development in non-obese people are still much debated. To reduce the global burden of diabetes, we need to understand why not all obese people develop T2D and not all those with T2D are obese. Moreover, through both an effective prevention and the implementation of an individualized clinical management in all people with diabetes, it is hoped that this will help to reduce this global burden. The purpose of this review is to take stock of current knowledge about the pathophysiology of diabetes not associated to obesity and to highlight which aspects are worthy of future studies.     

The Role of Hormonal Replacement Therapy in BRCA Mutated Patients: Lights and Shadows

Simple SummaryAdvances in molecular genetics have radically changed all aspects of cancer prevention, screening and treatment and, today, women who are suspected of being at risk of hereditary cancer should always undergo genetic counselling. Furthermore, today there is growing attention on the tumor suppressor genes BRCA 1 and BRCA2. In addition, there is growing attention on women who carry mutations of the tumor suppressor genes BRCA 1 and BRCA2 and undergo a prophylactic risk-reducing salpingo-oophorectomy. This paper explores the pathobiology of BRCA1\2 cancer genes in a translational perspective, focusing on molecular aspects of hormonal therapy in early menopausal women as well as on the latest evidence-based guidelines for clinicians. Physicians should counsel motivated patients who ask for relief from early menopausal symptoms about the risks and benefits of hormonal therapy, as well as tailoring and appropriate treatment for selected patients. AbstractAll cancers develop as a result of mutations in genes. DNA damage induces genomic instability and subsequently increases susceptibility to tumorigenesis. Women who carry mutations of BRCA 1 and BRCA2 genes have an augmented risk of breast and ovarian cancer and a markedly augmented probability of dying because of cancer compared to the general population. As a result, international guidelines recommend that all BRCA1\2 mutation carriers be offered risk-reducing bilateral salpingo-oophorectomy at an early age to reduce the risk of cancer and decrease the mortality rate of this high-risk population. NCCN guidelines recommend risk-reducing bilateral salpingo-oophorectomy in pre-menopausal women, between 35–40 years in BRCA1 mutation carriers and between 40–45 years in BRCA2 mutation carriers. Unfortunately, the well-documented reduction of cancer risk is counterbalanced by early sterility and premature ovarian failure with an early onset of secondary menopausal syndromes such as neuromotor, cardiovascular, cognitive and urogenital deficiency. Hormonal replacement therapy significantly compensates for hormonal deprivation and counteracts menopausal syndrome morbidity and mortality; however, some data suggest a possible correlation between hormonal medications and cancer risk, especially in BRCA1\2 carriers who undergo long-term regimens. Conversely, short-term treatment before the age of natural menopause does not appear to increase the cancer risk in BRCA1 mutation carriers without a personal history of breast cancer after prophylactic surgery. Few data are available on BRCA2 mutation carriers and more well-designed studies are needed. In conclusion, clinicians should propose short-term hormone replacement therapy to BRCA 1 carriers to counteract hormonal deprivation; personalized counselling should be offered to BRCA2 mutation carriers for a balance between the risks and benefits of the treatment.     

Monitoring Therapeutic Responses to Silicified Cancer Cell Immunotherapy Using PET/MRI in a Mouse Model of Disseminated Ovarian Cancer

Current imaging approaches used to monitor tumor progression can lack the ability to distinguish true progression from pseudoprogression. Simultaneous metabolic 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) offers new opportunities to overcome this challenge by refining tumor identification and monitoring therapeutic responses to cancer immunotherapy. In the current work, spatial and quantitative analysis of tumor burden were performed using simultaneous [¹⁸F]FDG-PET/MRI to monitor therapeutic responses to a novel silicified cancer cell immunotherapy in a mouse model of disseminated serous epithelial ovarian cancer. Tumor progression was validated by bioluminescence imaging of luciferase expressing tumor cells, flow cytometric analysis of immune cells in the tumor microenvironment, and histopathology. While PET demonstrated the presence of metabolically active cancer cells through [¹⁸F]FDG uptake, MRI confirmed cancer-related accumulation of ascites and tissue anatomy. This approach provides complementary information on disease status without a confounding signal from treatment-induced inflammation. This work provides a possible roadmap to facilitate accurate monitoring of therapeutic responses to cancer immunotherapies.     

Effect of high-pressure homogenisation on metabolic potential of Lacticaseibacillus paracasei 90: in vitro and in situ studies in fermented milk and semihard cheese

The influence of high-pressure homogenisation (HPH) at 100 MPa on Lacticaseibacillus paracasei 90 (L90) was studied in vitro and in situ (fermented milk and cheese). Lysis and injury signs were observed in cells treated with HPH, which were linked to the release of intracellular enzymes and changes in the metabolic activity of L90. HPH treatment led to a higher lactic acid content and lower pH and pyruvic acid levels in fermented milk. The microbiological and peptide profiles of cheeses were modified by using cells or cell-free extracts of L90. Finally, this study suggests that L90 could release bioactive peptides.     

Unraveling the role of shell thickness and pore size on the mechanical properties of ceramic-based macroporous structures

Macroporous structures are of interest for several technological applications such as catalysis, sensors, filters, membranes, batteries, energy conversion devices, structural colors, and reflective thermal barrier coatings. Ceramic-based inverse opal macroporous structures are especially interesting for high-temperature applications. However, the interrelation between the structural parameters, mechanical properties, and thermal stability of such structures is not yet clarified. In this work, we analyzed the mechanical properties as well as the thermal stability of aluminum oxide inverse opal three-dimensional macroporous structures with different macropore sizes and shell thicknesses produced by atomic layer deposition. Our results show that the structures’ thermal stability increased with increasing shell thickness and macropore size, however, their higher stability was not linked to their mechanical properties. To be able to explain this unexpected behavior, finite element modeling simulations were performed, showing that bending stresses became more pronounced with increasing shell thickness, potentially creating additional critical sites for crack initiation and consequent structural failure.