Selective Metal-ion Complexation of a Biomimetic Calix[6]arene Funnel Cavity Functionalized with Phenol or Quinone.

In the biomimetic context, many studies have evidenced the importance of the 1st and 2nd coordination sphere of a metal ion for controlling its properties. Here, we propose to evaluate a yet poorly explored aspect, which is the nature of the cavity that surrounds the metal labile site. Three calix[6]arene-based aza-ligands are compared, that differ only by the nature of cavity walls, anisole, phenol or quinone (LOMe , LOH and LQ ). Monitoring ligand exchange of their ZnII complexes evidenced important differences in the metal ion relative affinities for nitriles, halides or carboxylates. It also showed a possible sharp kinetic control on both, metal ion binding and ligand exchange. Hence, this study supports the observations reported on biological systems, highlighting that the substitution of an amino-acid residue of the enzyme active site, at remote distance of the metal ion, can have strong impacts on metal ion lability, substrate/product exchange or selectivity.

Bulk-to-Surface Proton-Coupled Electron Transfer Reactivity of the Metal-Organic Framework MIL-125.

Stoichiometric proton-coupled electron transfer (PCET) reactions of the metal-organic framework (MOF) MIL-125, Ti8O8(OH)4(bdc)6 (bdc = terephthalate), are described. In the presence of UV light and 2-propanol, MIL-125 was photoreduced to a maximum of 2( e-/H+) per Ti8 node. This stoichiometry was shown by subsequent titration of the photoreduced material with the 2,4,6-tri- tert-butylphenoxyl radical. This reaction occurred by PCET to give the corresponding phenol and the original, oxidized MOF. The high level of charging, and the independence of charging amount with particle size of the MOF samples, shows that the MOF was photocharged throughout the bulk and not only at the surface. NMR studies showed that the product phenol is too large to fit in the pores, so the phenoxyl reaction must have occurred at the surface. Attempts to oxidize photoreduced MIL-125 with pure electron acceptors resulted in multiple products, underscoring the importance of removing e- and H+ together. Our results require that the e- and H+ stored within the MOF architecture must both be mobile to transfer to the surface for reaction. Analogous studies on the soluble cluster Ti8O8(OOC tBu)16 support the notion that reduction occurs at the Ti8 MOF nodes and furthermore that this reduction occurs via e-/H+ (H-atom) equivalents. The soluble cluster also suggests degradation pathways for the MOFs under extended irradiation. The methods described are a facile characterization technique to study redox-active materials and should be broadly applicable to, for example, porous materials like MOFs.

Individual Trade-Offs Between Possible Benefits and Risks of Cancer Treatments: Results from a Stated Preference Study with Patients with Multiple Myeloma.

BACKGROUND: The objectives of this study were to elicit the preferences of patients with multiple myeloma regarding the possible benefits and risks of cancer treatments and to illustrate how such data may be used to estimate patients' acceptance of new treatments. PATIENTS AND METHODS: Patients with multiple myeloma from the cancer charity Myeloma UK were invited to participate in an online survey based on multicriteria decision analysis and swing weighting to elicit individual stated preferences for the following attributes: (a) 1-year progression-free survival (PFS, ranging from 50% to 90%), (b) mild or moderate toxicity for 2 months or longer (ranging from 85% to 45%), and (c) severe or life-threatening toxicity (ranging from 80% to 20%). RESULTS: A total of 560 participants completed the survey. The average weight given to PFS was 0.54, followed by 0.32 for severe or life-threatening toxicity and 0.14 for mild or moderate chronic toxicity. Participants who ranked severe or life-threatening toxicity above mild or moderate chronic toxicity (56%) were more frequently younger, working, and looking after dependent family members and had more frequently experienced severe or life-threatening side effects. The amount of weight given to PFS did not depend on any of the collected covariates. The feasibility of using the collected preference data to estimate the patients' acceptance of specific multiple myeloma treatments was demonstrated in a subsequent decision analysis example. CONCLUSION: Stated preference studies provide a systematic approach to gain knowledge about the distribution of preferences in the population and about what this implies for patients' acceptance of specific treatments. IMPLICATIONS FOR PRACTICE: This study demonstrated how quantitative preference statements from a large group of participants can be collected through an online survey and how such information may be used to explore the acceptability of specific treatments based on the attributes studied. Results from such studies have the potential to become an important new tool for gathering patient views and studying heterogeneity in preferences in a systematic way, along with other methods, such as focus groups and expert opinions.

Primary carbohydrate metabolism genes participate in heat-stress memory at the shoot apical meristem of Arabidopsis thaliana.

In plants, the shoot apical meristem (SAM) is essential for the growth of aboveground organs. However, little is known about its molecular responses to abiotic stresses. Here, we show that the SAM of Arabidopsis thaliana displays an autonomous heat-stress (HS) memory of a previous non-lethal HS, allowing the SAM to regain growth after exposure to an otherwise lethal HS several days later. Using RNA sequencing, we identified genes participating in establishing the SAM's HS transcriptional memory, including the stem cell (SC) regulators CLAVATA1 (CLV1) and CLV3, HEAT SHOCK PROTEIN 17.6A (HSP17.6A), and the primary carbohydrate metabolism gene FRUCTOSE-BISPHOSPHATE ALDOLASE 6 (FBA6). We demonstrate that sugar availability is essential for survival of plants at high temperature. HEAT SHOCK TRANSCRIPTION FACTOR A2 (HSFA2A) directly regulates the expression of HSP17.6A and FBA6 by binding to the heat-shock elements in their promoters, indicating that HSFA2 is required for transcriptional activation of SAM memory genes. Collectively, these findings indicate that plants have evolved a sophisticated protection mechanism to maintain SCs and, hence, their capacity to re-initiate shoot growth after stress release.

Myeloma Patient Value Mapping: A Discrete Choice Experiment on Myeloma Treatment Preferences in the UK.

BACKGROUND: Myeloma is an incurable life-threatening hematological cancer. Recent treatment developments have seen improvements in survival; however, while patients are living longer, they are living with symptoms and treatment side effects. OBJECTIVE: To evaluate myeloma patients' preferences for treatment using a discrete choice experiment (DCE). This study set out to define the relative importance of key treatment attributes, characterize the risk-benefit trade-offs in patients' decision-making, and to analyze the predictive power of basic demographic factors. METHODS: Four hundred seventy-five myeloma patients in the UK were invited to participate by Myeloma UK. Data were collected using DCEs through an online survey. The DCEs presented patients with 10 choice scenarios, each with 2 treatment options described by 7 attributes, and a "no treatment" option. The DCE data were modelled using a latent class model (LCM). The effects of demographic characteristics were also examined. RESULTS: Not surprisingly, average survival was most important to all patients but there were significant contrasts between the class preferences. The LCM revealed two classes of patients. Patients in Class 1 placed greater importance on average survival and mild-to-moderate side effects, whereas patients in Class 2 focused on the mode of administration and the average out-of-pocket costs. Patients living with others and those diagnosed in the last 5 years were more likely to be in Class 1. CONCLUSION: Different treatment features were not valued equally among all myeloma patients. This has important implications for healthcare policy decisions and could be used to guide decisions around the value of new myeloma medicines.

Physiological Profiling of Embryos and Dormant Seeds in Two Arabidopsis Accessions Reveals a Metabolic Switch in Carbon Reserve Accumulation.

In flowering plants, sugars act as carbon sources providing energy for developing embryos and seeds. Although most studies focus on carbon metabolism in whole seeds, knowledge about how particular sugars contribute to the developmental transitions during embryogenesis is scarce. To develop a quantitative understanding of how carbon composition changes during embryo development, and to determine how sugar status contributes to final seed or embryo size, we performed metabolic profiling of hand-dissected embryos at late torpedo and mature stages, and dormant seeds, in two Arabidopsis thaliana accessions with medium [Columbia-0 (Col-0)] and large [Burren-0 (Bur-0)] seed sizes, respectively. Our results show that, in both accessions, metabolite profiles of embryos largely differ from those of dormant seeds. We found that developmental transitions from torpedo to mature embryos, and further to dormant seeds, are associated with major metabolic switches in carbon reserve accumulation. While glucose, sucrose, and starch predominantly accumulated during seed dormancy, fructose levels were strongly elevated in mature embryos. Interestingly, Bur-0 seeds contain larger mature embryos than Col-0 seeds. Fructose and starch were accumulated to significantly higher levels in mature Bur-0 than Col-0 embryos, suggesting that they contribute to the enlarged mature Bur-0 embryos. Furthermore, we found that Bur-0 embryos accumulated a higher level of sucrose compared to hexose sugars and that changes in sucrose metabolism are mediated by sucrose synthase (SUS), with SUS genes acting non-redundantly, and in a tissue-specific manner to utilize sucrose during late embryogenesis.

Sodium-coupled electron transfer reactivity of metal-organic frameworks containing titanium clusters: the importance of cations in redox chemistry.

Stoichiometric reduction reactions of two metal-organic frameworks (MOFs) by the solution reagents (M = Cr, Co) are described. The two MOFs contain clusters with Ti8O8 rings: Ti8O8(OH)4(bdc)6; bdc = terephthalate (MIL-125) and Ti8O8(OH)4(bdc-NH2)6; bdc-NH2 = 2-aminoterephthalate (NH2-MIL-125). The stoichiometry of the redox reactions was probed using solution NMR methods. The extent of reduction is greatly enhanced by the presence of Na+, which is incorporated into the bulk of the material. The roughly 1 : 1 stoichiometry of electrons and cations indicates that the storage of e- in the MOF is tightly coupled to a cation within the architecture, for charge balance.

Chemoselective guest-triggered shaping of a polynuclear CuII calix[6]complex into a molecular host.

A new calix[6]arene scaffold bearing a tris-imidazole binding site at the small rim and three tetradentate aza ligands at the large rim was synthesized. The system binds three CuII ions at the large rim sites and is unable to bind a fourth one, which remains in solution. The charge repulsion between the complexes, together with the flexibility of the scaffold, disorganizes the small rim site for binding and prevents its use for host-guest studies. Although the presence of MeCN or DMF guests does not alter this state, the addition of a heptylamine guest, which further displays Brønsted basicity, restores its receptor ability by stabilizing the extra CuII ion at the tris-imidazole site with concomitant guest encapsulation and binding of an exo hydroxo ligand. This chemoselective nuclearity switch yields a tetranuclear complex in which the guest backbone is preorganized in front of three potentially reactive Cu(ii) complexes, reminiscent of polynuclear CuII enzyme active sites.

Estudo clínico, citogenético e molecular nas síndromes de Prader-Willi e Angelman / Clinical, cytogenetical and molecular studies in Prader-Willi and Angelman syndromes

A Síndrome de Prader-Willi (SPW) e a Síndrome de Angelman (SA) säo doenças neurogenéticas consideradas como exemplos do fenômeno de impressäo genômica, em seres humano, estando relacionadas com alteraçöes envolvendo a regiäo cromossômica 15q11-13. As alteraçöes genéticas predominantes, na SPW, säo deleçöes na regiäo 15q11-13, de origem paterna e dissomia uniparental materna e, na SA, encontram-se deleçöes na regiäo 15q11-13 materna e dissomia uniparental paterna. Estudamos 5 pacientes com suspeita clínica de SPW e 4 pacientes com suspeita clínica de SA, atendidos no Setor de Genética Médica do Hospital das Clínicas da FMRP-USP, com o objetivo de estabelecer o diagnóstico clínico e etiológico nessa amostra. Para isso, utilizamos citogenética convencional, estudo de metilaçäo por Southern blotting com a sonda KB17 (ilha CpG do gene SNRPN), após digestäo com as enzimas de restriçäo Xba I e Not I, e análise de polimorfismos de repetiçäo (CA)n por PCR, usando os primers 196 e IR4-3R. Dos 9 pacientes avaliados, todos tiveram avaliaçäo citogenética convencional normal. Foram confirmados molecularmente 1 caso de SPW por deleçäo nova, 1 caso de SPW por dissomia uniparenteal materna e 1 caso de SPW em que a causa genética näo pode ser esclarecida pela análise de polimorfismo com os primers usados. Foram confirmados, molecularmente, 2 casos de SA, ambos por deleçäo nova na regiäo 15q11-13 e, 1 caso de SA, cuja clínica é extremamente sugestiva, teve resultado molecular normal, podendo-se sugerir uma mutaçäo de ponto no gene responsável pela SA.